Tricyclic heterocyclic compounds as sting activators

ABSTRACT

The present application provides tricyclic heterocyclic compounds that activate the STING pathway to produce interferons, which are useful in the treatment of various diseases including infectious diseases and cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 62/676,810, filed May 25, 2018, 62/730,610, filed Sep. 13, 2018, and62/841,587, filed May 1, 2019, the disclosure of each of which isincorporated herein by reference in its entirety.

TECHNICAL FIELD

The present application provides tricyclic heterocyclic compounds thatactivate the STING pathway to produce interferons, which are useful inthe treatment of various diseases including infectious diseases andcancer.

BACKGROUND

The innate immunity is the first line of defense against infection fromforeign microorganisms including bacteria, viruses, parasites and otherinfectious threats, but it also responds to certain danger signalsassociated with cellular or tissue damage. This response is initiated byactivation of so-called pattern recognition receptors that can detectdifferent forms of foreign antigens, i.e. nucleic acids, peptides,carbohydrates, and more, which then lead to production of interferons,proinflammatory chemokines and cytokines, and anti-microbial peptides tofight infection (Palm and Medzhitov, Immunol Rev (2009) 227:221-233;Takeuchi and Akira, Immunol Rev (2009) 227:75-86; Beutler, Blood (2009)113:1399-1407). STING (stimulator of interferon genes), also known asMITA, MPYS, ERIS, and TMEM173, is one of such pattern recognitionreceptors in the innate immune response that could detect cytosolicnucleic acids (Ishikawa and Barber, Nature (2008) 455:674-678). Directbinding of STING to its ligands induces a conformational change of thecomplex resulting in a downstream signaling cascade involving TBK1activation, IRF-3 phosphorylation, and production of type I IFNs andother proinflammatory cytokines, such as TNF, IL-6 and IFNγ (Ishikawaand Barber, Nature (2008) 455:674-678).

Type I interferons play a central role in orchestrating host anti-viralresponse through inhibiting viral replication in infected cells,activating and enhancing antigen presentation and triggering theadaptive immune response through direct and indirect action on T and Bcells (McNab et al, Nat Rev Immunol (2015) 15:87-103; Crosse et al, JInnate Immun (2018) 10:85-93). Therefore, this cytokine acts as a masterregulator whose induction in the early stages of viral infectionmodulates downstream signaling cascades that promote bothpro-inflammatory and anti-inflammatory responses. Thus type I IFNs havebeen evaluated as a therapeutic agent for chronic viral infection suchas HCV and HIV (Enomoto and Nishiguchi, World J Hepatol (2015)7:2681-2687; Azzoni et al, J Infect Dis (2013) 207:213-222; Lane et al,Ann Intern Med (1990) 112:805-11).

The use of type I interferons (IFNs) (the IFNα family and IFNβ) aspotential antitumor agents has also been investigated (Kirkwood, SeminOncol (2002) 29:18-26; Tarhini et al, J Immunol (2012) 189:3789-3793).IFNs have multiple anticancer mechanisms that include: direct inhibitionon tumor cell proliferation and angiogenesis; induction oftumor-specific cytotoxic T-cells; plus other immunoregulatory effects onantibody production, natural killer (NK) cell activation, macrophagefunction, delayed-type hypersensitivity, and major histocompatibilitycomplex antigen expression (Hervas-Stubbs et al, Clin Cancer Res (2011)17:2619-2627; Vannucchi et al, Curr Med Chem (2007) 14:667-679).Anticancer activity of type I IFNs has been demonstrated in patientswith hematological malignancies (e.g., hairy cell leukemia) and solidtumors (e.g., renal cell carcinoma and malignant melanoma) (Quesada etal, N Engl J Med (1984) 310:15-18; Pizzocaro et al, J Clin Oncol (2001)19:425-431; Garbe and Eigentler, Melanoma Res (2007) 17:117-127),however, the results and overall efficacy have been modest.

This may be due to intrinsic resistance to IFN-induced cell death, tothe short half-life (˜30 minutes) of intravenously or subcutaneouslydosed IFN, to dose-limiting systemic toxicities, and/or to thedevelopment of neutralizing antibodies against recombinant IFN protein.Thus, the development of an agent like a STING agonist to induceproduction of type I interferons will be of interest to the field.Currently, there are two different classes of STING agonists: cyclicdinucleotide and small molecule.

Cyclic dinucleotides (CDNs) can directly bind and activate STING, andthe complex of bacterial CDN and STING has been confirmed by X-raycrystallography recently (Burdette and Vance, Nat Immunol (2013)14:19-26). In mammalian cells, the primary sensor of cyclic doublestranded DNA (dsDNA), namely cyclic GMP-AMP synthetase (cGAS), canconvert those cyclic dsDNA into a mammalian CDN cGAMP (cyclic guanosinemonophosphate-adenosine monophosphate; Gao et al, Cell (2013)154:748-762). The interaction of cGAMP and STING has also been confirmedby X-ray crystallography (Cai et al, Mol Cell (2014) 54:289-296).Synthetic derivatives of cGAMP have been synthesized and showedexcellent cellular potency to activate both mouse and human STING invitro, as well as demonstrated good anti-tumor efficacy in preclinicalmouse models (Corrales et al, Cell Rep (2015) 11:1018-1030).

Small molecules that can activate STING have also been identified, DMXAA(5,6-dimethylxanthenone-4-acetic acid) and CMA(10-carboxymethyl-9-acridanone) (Perera et al, J Immunol (1994)153:4684-4697; Kramer et al, Antimicrob Agents Chemother (1976)9:233-238). These two chemically-unrelated compounds can activate theSTING pathway, and block multiple viruses from replication (Guo et al,Agents Chemother (2015) 59:1273-1281; Cheng et al, Am J Respir Cell MolBiol (2011) 45:480-488). Intriguingly, DMXAA demonstrates excellentanti-tumor activity in preclinical mouse models by priming CD8+ T cellsresponses to promote rejection of established tumors in aSTING-dependent manner, inducing tumor necrosis through disruption oftumor vasculature, as well as augmenting cancer vaccine effect (Corraleset al, Cell Rep (2015) 11:1018-1030; Wallace et al, Cancer Res (2007)67:7011-7019; Tang et al, Plos One (2013) 8:1-6). Unfortunately, bothDMXAA and CMA were found to only bind and activate mouse STING, but nothuman STING (Caviar et al, EMBO J(2013) 32:1440-1450; Kim et al, ACSChem Biol (2013) 8:1396-1401).

Hence, there is a need to develop small molecule entities that canactivate human STING and induce upregulation of IRF3 and NFκB pathway,which can later lead to production of interferons and otherproinflammatory cytokines and chemokines. This type of immunomodulatingagents may be useful not only in infectious disease to activate innateimmunity, but also in cancer, and as vaccine adjuvants. This applicationis directed to this need and others.

SUMMARY

The present invention relates to, inter alia, compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein constituentmembers are defined herein.

The present invention further provides pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides methods of activating STING,comprising contacting the receptor with a compound of Formula (I), or apharmaceutically acceptable salt thereof.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for the preparation of amedicament for use in any of the methods described herein.

DETAILED DESCRIPTION Compounds

The present application provides, inter alia, compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, or 5-10 membered heteroaryl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2, 3, or 4independently selected R⁸ groups;

U is N or CR^(U);

V is N or CR^(V);

W is N or CR^(W);

Q is N or CR^(Q);

wherein U═V—W=Q is selected from CR^(U)═CR^(V)—CR^(W)═CR^(Q),N═CR^(V)—CR^(W)═CR^(Q), CR^(U)═N—CR^(W)═CR^(Q), CR^(U)═CR^(V)—N═CR^(Q),CR^(U)═CR^(V)—CR^(W)═N, N═N—CR^(W)═CR^(Q), CR^(U)═N—N═CR^(Q),CR^(U)═CR^(V)—N═N, N═CR^(V)—CR^(W)═N, N═CR^(V)—N═CR^(Q),CR^(U)═N—CR^(W)═N, N═N—CR^(W)═N, and N═CR^(V)—N═N;

R^(U), R^(V), R^(W), and R^(Q) are each independently selected from H,D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, OR^(a), SR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d),C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b), NR^(c)C(═O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), andS(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by1, 2, 3, or 4 independently selected R⁸ groups;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selected R⁸groups;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R⁸ groups;

each R^(e) is independently selected from H, CN, OH, C₁₋₄ alkyl, andC₁₋₄ alkoxy;

each R⁸ is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a8), SR^(a8), C(═O)R^(b8),C(═O)NR^(c8)R^(d8), C(═O)OR^(d8), OC(═O)R^(b8), OC(═O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8), NR^(c8)C(═O)OR^(b8),NR^(c8)C(═O)NR^(c8)R^(d8), C(═NR^(e))R^(b8), C(═NR^(e))NR^(c8)R^(d8),NR^(c8)C(═NR^(e))NR^(c8)R^(d8), NR^(c8)S(═O)₂R^(c8),NR^(c8)S(═O)₂NR^(c8)R^(d8), S(═O)₂R^(b8), and S(═O)₂NR^(c8)R^(d8),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selected R¹⁰groups;

each R^(a8), R^(c8), and R^(d8) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR¹⁰ groups;

each R^(b8) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R¹⁰ groups;

each R¹⁰ is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a10), SR^(a10), C(═O)R^(b10),C(═O)NR^(c10)R^(d10), C(═O)OR^(a10), OC(═O)R^(b10),OC(═O)NR^(c10)R^(d10), NR^(c10)R^(d10), NR^(c10)C(═O)R^(b10),NR^(c10)C(═O)OR^(b10), NR^(c10)C(═O)NR^(c10)R^(d10), C(═NR^(e))R^(b10),C(═NR^(e))NR^(c10)R^(d10), NR^(c10)C(═NR^(e))NR^(c10)R^(d10),NR^(c10)S(═O)₂R^(b10), NR^(c10)S(═O)₂NR^(c10)R^(d10), S(═O)₂R^(b10), orS(═O)₂NR^(c10)R^(d10), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(G) groups;

each R^(a10), R^(c10), and R^(d10) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) groups;

each R^(b10) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R^(G) groups;

X is N or CR^(X);

Y is N or CR^(Y);

Z is N or CR^(Z);

wherein i) X, Y and Z are CR^(X), CR^(Y), and CR^(Z) respectively, orii) only one of X, Y and Z is N, or iii) only two of X, Y and Z are N;R^(X), R^(Y), and R^(Z) are each independently selected from H, D, halo,CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a0), SR^(a0), C(═O)R^(b0), C(═O)NR^(c0)R^(d0), C(═O)OR^(a0),OC(═O)R^(b0), OC(═O)NR^(c0)R^(d0), NR^(c0)R^(d0), NR^(c0)C(═O)R^(b0),NR^(c0)(═O)OR^(b0), NR^(c0)(═O)NR^(c0)R^(d0), C(═NR^(e))R^(b0),C(═NR^(e))NR^(c0)R^(d0), NR^(c0)(═NR^(e))NR^(c0)R^(d0),NR^(c0)S(═O)₂R^(b0), NR^(c0)S(═O)₂NR^(c0)R^(d0), S(═O)₂R^(b0), andS(═O)₂NR^(c0)R^(d0), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by1, 2, 3, or 4 independently selected R^(G) groups;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) groups;

each R^(b0) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(G) groups;

Ring moiety A is selected from C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl, and 5-10 membered heteroaryl, each of whichis optionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

Ring moiety B is selected from C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl, and 5-10 membered heteroaryl, each of whichis optionally substituted by 1, 2, 3, or 4 independently selected R^(B)groups;

n is 0 or 1;

m is 0 or 1;

s is 0 or 1;

wherein n+m+s=1 or 2;

when n is 1, R¹ and R² taken together form a linking group L¹;

when m is 1, one of R^(A) and one of R^(B) taken together form a linkinggroup L²;

when s is 1, R^(Q) and R⁴ taken together form a linking group L³;

L¹, L², and L³ are each independently selected from -R-R-, -R-R-R-,-Cy-, -R-Cy-, -Cy-R, -R-Cy-R-, -R-R-Cy-, -Cy-R-R-, and -Cy-R-Cy-;

each R is independently M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, C₁₋₆ alkylene-M, M-C₁₋₆ alkylene, C₁₋₆ alkylene-M-C₁₋₆alkylene, M-C₁₋₆ alkylene-M, C₂₋₆ alkenylene-M, M-C₂₋₆ alkenylene, C₂₋₆alkenylene-M-C₂₋₆ alkenylene, M-C₂₋₆ alkenylene-M, C₂₋₆ alkynylene-M,M-C₂₋₆ alkynylene, C₂₋₆ alkynylene-M-C₂₋₆ alkynylene, or M-C₂₋₆alkynylene-M, wherein each of said C₁₋₆ alkylene, C₂₋₆ alkenylene, andC₂₋₆ alkynylene is optionally substituted by 1, 2, 3, or 4 groupsindependently selected R^(G) groups;

each Cy is independently selected from C₃₋₁₄ cycloalkyl, phenyl, 4-14membered heterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(G)groups;

each M is independently —O—, —S—, —C(O)—, —C(O)NR^(L)—, —C(O)O—,—OC(O)—, —OC(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—,—NR^(L)C(O)NR^(L)—, —NR^(L)S(O)₂—, —S(O)₂—, —S(O)₂NR^(L)—, or—NR^(L)S(O)₂NR^(L)—; provided that when M is attached to a nitrogenatom, then M is selected from —C(O)—, —C(O)NR^(L)—, —C(O)O—, —S(O)₂—, or—S(O)₂NR^(L)—;

each R^(L) is independently selected from H, C₁₋₃ alkyl, C₂₋₃ alkenyl,C₂₋₃ alkynyl, and C₁₋₃ haloalkyl;

each R^(A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1),NR^(c1)S(═O)₂R^(b2), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), andS(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(A1) groups;

each R^(B) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a2), SR^(a2), C(═O)R^(b2), C(═O)NR^(c2)R^(d2), C(═O)OR^(a2),OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2),NR^(c2)C(═O)OR^(b2), NR^(c2)C(═O)NR^(c2)R^(d2), C(═NR^(e))R^(b2),C(═NR^(e))NR^(c2)R^(d2), NR^(c2)C(═NR^(e))NR^(c2)R^(d2),NR^(c2)S(═O)₂R^(b2), NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)₂R^(b2), andS(═O)₂NR^(c2)R^(d2), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(B1) groups;

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(A1) groups;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(A1) groups;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(B1) groups;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(B1) groups;

each R^(A1) and R^(B1) is independently selected from H, halo, CN, NO₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a12), SR^(a12), C(═O)R^(b12), C(═O)NR^(c12)R^(d12), C(═O)OR^(a12),OC(═O)R^(b12), OC(═O)NR^(c12)R^(d12), NR^(c12)R^(d12),NR^(c12)C(═O)R^(b12) NR^(c12)C(═O)OR^(b12),NR^(c12)C(═O)NR^(c12)R^(d12), C(═NR^(e))R^(b12),C(═NR^(e))NR^(c12)R^(d12), NR^(c12)C(═NR^(e))NR^(c12)R^(d12),NR^(c12)S(═O)₂R^(b12), NR^(c12)S(═O)₂NR^(c12)R^(d12), S(═O)₂R^(b12), andS(═O)₂NR^(c12)R^(d12), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(G) groups;

each R^(a12), R^(c12), and R^(d12) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) groups;

each R^(b12) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R^(G) groups;

R² is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, or 5-10 membered heteroaryl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(2a) groups;

R³ is H, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

R⁴ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, OR^(a4), SR^(a4), C(═O)R^(b4),C(═O)NR^(c4)R^(d4), C(═O)OR^(a4), OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)OR^(b4),NR^(c4)C(═O)NR^(c4)R^(d4), C(═NR^(e))R^(b4), C(═NR^(e))NR^(c4)R^(d4),NR^(c4)C(═NR^(e))NR^(c4)R^(d4), NR^(c4)S(═O)₂R^(b4),NR^(c4)S(═O)₂NR^(c4)R^(d4), S(═O)₂R^(b4), or S(═O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(4a) groups;

R⁵ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, OR^(a5), SR^(a5), C(═O)R^(b5),C(═O)NR^(c5)R^(d5), C(═O)OR^(a5), OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)OR^(b5),NR^(c5)C(═O)NR^(c5)R^(d5), C(═NR^(e))R^(b5), C(═NR^(e))NR^(c5)R^(d5),NR^(c5)C(═NR^(e))NR^(c5)R^(d5), NR^(c5)S(═O)₂R^(b5),NR^(c5)S(═O)₂NR^(c5)R^(d5), S(═O)₂R^(b5), or S(═O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(5a) groups;

R⁶ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, OR^(a6), SR^(a6), C(═O)R^(b6),C(═O)NR^(c6)R^(d6), C(═O)OR^(a6), OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6), NR^(c6)C(═O)OR^(b6),NR^(c6)C(═O)NR^(c6)R^(d6), C(═NR^(e))R^(b6), C(═NR^(e))NR^(c6)R^(d6),NR^(c6)C(═NR^(e))NR^(c6)R^(d6), NR^(c6)S(═O)₂R^(b6),NR^(c6)S(═O)₂NR^(c6)R^(d6), S(═O)₂R^(b6), or S(═O)₂NR^(c6)R^(d6),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(6a) groups;

R⁷ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, OR^(a7), SR^(a7), C(═O)R^(b7),C(═O)NR^(c7)R^(d7), C(═O)OR^(a7), OC(═O)R^(b7), OC(═O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(═O)R^(b7), NR^(c7)C(═O)OR^(b7),NR^(c7)C(═O)NR^(c7)R^(d7), C(═NR^(e))R^(b7), C(═NR^(e))NR^(c7)R^(d7),NR^(c7)C(═NR^(e))NR^(c7)R^(d7), NR^(c7)S(═O)₂R^(b7),NR^(c7)S(═O)₂NR^(c7)R^(d7), S(═O)₂R^(b7), or S(═O)₂NR^(c7)R^(d7),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(7a) groups;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4a) groups;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(4a) groups;

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5a) groups;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(5a) groups;

each R^(a6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(6a) groups;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynylC₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(6a) groups;

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(7a) groups;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(7a) groups;

each R^(2a), R^(4a), R^(5a), R^(6a), and R^(7a) are independentlyselected from H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a9), SR^(a9), C(═O)R^(b9), C(═O)NR^(c9)R^(d9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NR^(c9)C(═O)OR^(b9), NR^(c9)C(═O)NR^(c9)R^(d9), C(═NR^(e))R^(b9),C(═NR^(e))NR^(c9)R^(d9), NR^(c9)C(═NR^(e))NR^(c9)R^(d9),NR^(c9)S(═O)₂R^(b9), NR^(c9)S(═O)₂NR^(c9)R^(d9), S(═O)₂R^(b9), andS(═O)₂NR^(c9)R^(d9), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R¹¹ groups;

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR¹¹ groups;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

each R¹¹ is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a11), SR^(a11), C(═O)R^(b11),C(═O)NR^(c11)R^(d11), C(═O)OR^(a11), OC(═O)R^(b11),OC(═O)NR^(c11)R^(d11), NR^(c11)R^(d11), NR^(c11)C(═O)R^(b11),NR^(c11)C(═O)OR^(b11), NR^(c11)C(═O)NR^(c11)R^(d11), C(═NR^(e))R^(b11),C(═NR^(e))NR^(c11)R^(d11), NR^(c11)C(═NR^(e))NR^(c11)R^(d11),NR^(c11)S(═O)₂R^(b11), NR^(c11)S(═O)₂NR^(c11)R^(d11), S(═O)₂R^(b11), andS(═O)₂NR^(c11)R^(d11), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(G) groups;

each R^(a11), R^(c11), and R^(d11) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) groups;

each R^(b11) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R^(G) groups;

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments, the compound is a compound of Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R^(U), R^(V), and R^(W) are each independently selected from H, D, OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

R^(Q) is selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, —C₁₋₆alkylene-R⁸⁰, —C₁₋₆ alkylene-R⁹⁰, —C₁₋₆ alkylene-OR⁸⁰, —C₁₋₆alkylene-NHR⁸⁰, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a), OR^(f), SR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d),C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b), NR^(c)C(═O)NR^(c)R^(d),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), andS(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by1, 2, 3, or 4 independently selected R⁸ groups;

R^(a), R^(c), and R^(d) are each independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selected R⁸groups;

R^(b) is selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R⁸ groups;

each R^(e) is independently selected from H, CN, OH, C₁₋₄ alkyl, andC₁₋₄ alkoxy;

R^(f) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, which are eachoptionally substituted with 1 substituent selected from R⁸⁰, —OR⁸⁰, R⁹⁰,and —NHR⁸⁰;

each R⁸ is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a8), SR^(a8), C(═O)R^(b8),C(═O)NR^(c8)R^(d8), C(═O)OR^(a8), OC(═O)R^(b8), OC(═O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8), NR^(c8)C(═O)OR^(b8),NR^(c8)C(═O)NR^(c8)R^(d8), C(═NR^(e))R^(b8), C(═NR^(e))NR^(c8)R^(d8),NR^(c8)C(═NR^(e))NR^(c8)R^(d8), NR^(c8)S(═O)₂R^(b8),NR^(c8)S(═O)₂NR^(c8)R^(d8), S(═O)₂R^(b8), and S(═O)₂NR^(c8)R^(d8),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selected R¹⁰groups;

each R^(a8), R^(c8), and R^(d8) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR¹⁰ groups;

each R^(b8) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R¹⁰ groups;

each R¹⁰ is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a10), SR^(a10), C(═O)R^(b10),C(═O)NR^(c10)R^(d10), C(═O)OR^(a10), OC(═O)R^(b10),OC(═O)NR^(c10)R^(d10), NR^(c10)R^(d10), NR^(c10)C(═O)R^(b10),NR^(c10)C(═O)OR^(b10), NR^(c10)C(═O)NR^(c10)R^(d10), C(═NR^(e))R^(b10),C(═NR^(e))NR^(c10)R^(d10), NR^(c10)C(═NR^(e))NR^(c10)R^(d10),NR^(c10)S(═O)₂R^(b10), NR^(c10)S(═O)₂NR^(c10)R^(d10), S(═O)₂R^(b10), orS(═O)₂NR^(c10)R^(d10), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(G) groups;

each R^(a10), R^(c10), and R^(d10) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) groups;

each R^(b10) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R^(G) groups;

R⁸⁰ is a linear peptide chain having 2-6 amino acids, which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents;

R⁹⁰ is a linear chain of formula —(O—C₂₋₄ alkylene)_(z)-R^(G), wherein zis 1, 2, 3, 4, 5, or 6;

Y is N or CRY;

Z is N or CR^(Z);

R^(X), R^(Y), and R^(Z) are each independently selected from H, D, halo,CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, andC₃₋₄ cycloalkyl;

Ring moiety A is 5-membered heteroaryl, which is optionally substitutedby 1, 2, 3, or 4 independently selected R^(A) groups;

Ring moiety B is 5-membered heteroaryl, which is optionally substitutedby 1, 2, 3, or 4 independently selected R^(B) groups;

L¹ is selected from -R-R- and -R-R-R-;

each R is independently M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, C₁₋₆ alkylene-M, M-C₁₋₆ alkylene, C₁₋₆ alkylene-M-C₁₋₆alkylene, M-C₁₋₆ alkylene-M, C₂₋₆ alkenylene-M, M-C₂₋₆ alkenylene, C₂₋₆alkenylene-M-C₂₋₆ alkenylene, M-C₂₋₆ alkenylene-M, C₂₋₆ alkynylene-M,M-C₂₋₆ alkynylene, C₂₋₆ alkynylene-M-C₂₋₆ alkynylene, or M-C₂₋₆alkynylene-M, wherein each of said C₁₋₆ alkylene, C₂₋₆ alkenylene, andC₂₋₆ alkynylene is optionally substituted by 1, 2, 3, or 4 groupsindependently selected R^(G) groups;

each M is independently —O—, —S—, —C(O)—, —C(O)NR^(L)—, —C(O)O—,—OC(O)—, —OC(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—,—NR^(L)C(O)NR^(L)—, —NR^(L)S(O)₂₋, —S(O)₂—, —S(O)₂NR^(L)—, or—NR^(L)S(O)₂NR^(L)—; provided that when M is attached to a nitrogenatom, then M is selected from —C(O)—, —C(O)NR^(L)—, —C(O)O—, —S(O)₂—, or—S(O)₂NR^(L)—;

each R^(L) is independently selected from H, C₁₋₃ alkyl, C₂₋₃ alkenyl,C₂₋₃ alkynyl, and C₁₋₃ haloalkyl;

each R^(A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₄cycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(G) groups;

each R^(B) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₄cycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(G) groups;

R⁵, R⁶, and R⁷ are each independently selected from H, D, OH, NO₂, CN,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆alkyl, HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl,C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino;

R⁴ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, —C₁₋₆ alkylene-R⁸⁰, —C₁₋₆alkylene-R⁹⁰, —C₁₋₆ alkylene-OR⁸⁰, —C₁₋₆ alkylene-NHR⁸⁰, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a4), OR^(f4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4),C(═O)OR^(a4), OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)OR^(b4), NR^(c4)C(═O)NR^(c4)R^(d4),C(═NR^(e))R^(b4), C(═NR^(e))NR^(c4)R^(d4),NR^(c4)C(═NR^(e))NR^(c4)R^(d4), NR^(c4)S(═O)₂R^(b4),NR^(c4)S(═O)₂NR^(c4)R^(d4), S(═O)₂R^(b4), or S(═O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(4a) groups;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4a) groups;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(4a) groups;

R^(f4) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, which are eachoptionally substituted with 1 substituent selected from R⁸⁰, R⁹⁰, —OR⁸⁰,and —NHR⁸⁰;

each R^(4a) is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a9), SR^(a9), C(═O)R^(b9),C(═O)NR^(c9)R^(d9), C(═O)OR^(a9), OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9),NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9), NR^(c9)C(═O)OR^(b9),NR^(c9)C(═O)NR^(c9)R^(d9), C(═NR^(e))R^(b9), C(═NR^(e))NR^(c9)R^(d9),NR^(c9)C(═NR^(e))NR^(c9)R^(d9), NR^(c9)S(═O)₂R^(b9),NR^(c9)S(═O)₂NR^(c9)R^(d9), S(═O)₂R^(b9), and S(═O)₂NR^(c9)R^(d9),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selected R¹¹groups;

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR¹¹ groups;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

R^(f4) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, which are eachoptionally substituted with 1 substituent selected from R⁸⁰, —OR⁸⁰, and—NHR⁸⁰;

each R¹¹ is independently selected from H, halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a11), SR^(a11), C(═O)R^(b11),C(═O)NR^(c11)R^(d11), C(═O)OR^(a11), OC(═O)R^(b11),OC(═O)NR^(c11)R^(d11), NR^(c11)R^(d11), NR^(c11)C(═O)R^(b11),NR^(c11)C(═O)OR^(b11), NR^(c11)C(═O)NR^(c11)R^(d11), C(═NR^(e))R^(b11),C(═NR^(e))NR^(c11)R^(d11), NR^(c11)C(═NR^(e))NR^(c11)R^(d11)NR^(c11)S(═O)₂R^(b11), NR^(c11)S(═O)₂NR^(c11)R^(d11), S(═O)₂R^(b11), andS(═O)₂NR^(c11)R^(d11), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(G) groups;

each R^(a11), R^(c11), and R^(d11) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) groups;

each R^(b11) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R^(G) groups; and

each R^(G) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments, R⁸⁰ is a linear peptide chain having 2-6 aminoacids.

In some embodiments, R⁸⁰ is a linear peptide chain having 2-4 aminoacids.

In some embodiments, R⁸⁰ is a linear peptide chain having 2-6 aminoacids, wherein the amino acids are independently selected from alanine(Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine(cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine(His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met),phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr),tryptophan (Trp), tyrosine (Tyr), and valine (Val). In some embodiments,R⁸⁰ is a linear peptide chain having 2-6 amino acids independentlyselected from Asp, Arg, Glu, His, Lys, Ser, Thr, Asn, and Gln. In someembodiments, R⁸⁰ is a linear peptide chain having 2-6 amino acidsindependently selected from Asp, Arg, Glu, His, and Lys. In someembodiments, R⁸⁰ is a linear peptide chain having 2-6 amino acidsindependently selected from Asp and Arg. In some embodiments, R⁸⁰ is alinear peptide chain having 2-4 amino acids independently selected fromAsp, Arg, Glu, His, Lys, Ser, Thr, Asn, and Gln. In some embodiments,R⁸⁰ is a linear peptide chain having 2-4 amino acids independentlyselected from Asp, Arg, Glu, His, and Lys. In some embodiments, R⁸⁰ is alinear peptide chain having 2-4 amino acids independently selected fromAsp and Arg.

In some embodiments, U═V—W=Q is selected fromCR^(U)═CR^(V)—CR^(W)═CR^(Q), N═CR^(V)—CR^(W)═CR^(Q),CR^(U)═N—CR^(W)═CR^(Q), CR^(U)═CR^(V)—N═CR^(Q), CR^(U)═CR^(V)—CR^(W)═N,N═N—CR^(W)═CR^(Q), CR^(U)═N—N═CR^(Q), CR^(U)═CR^(V)—N═N,N═CR^(V)—CR^(W)═N, N═CR^(V)—N═CR^(Q), and CR^(U)═N—CR^(W)═N.

In some embodiments, U═V—W=Q is selected fromCR^(U)═CR^(V)—CR^(W)═CR^(Q), N═CR^(V-)CR^(W)═CR^(Q),CR^(U)═N—CR^(W)═CR^(Q), CR^(U)═CR^(V)—N═CR^(Q), andCR^(U)═CR^(V)—CR^(W)═N.

In some embodiments, U═V—W=Q is selected from N═N—CR^(W)═CR^(Q),CR^(U)═N—N═CR^(Q), CR^(U)═CR^(V)—N═N, N═CR^(V)—CR^(W)═N,N═CR^(V)—N═CR^(Q), and CR^(U)═N—CR^(W)═N.

In some embodiments, U═V—W=Q is CR^(U)═CR^(V)—CR^(W)═CR^(Q).

In some embodiments, U═V—W=Q is N═CR^(V)—CR^(W)═CR^(Q).

In some embodiments, U═V—W=Q is CR^(U)═N—CR^(W)═CR^(Q).

In some embodiments, U═V—W=Q is CR^(U)═CR^(V)—N═CR^(Q).

In some embodiments, U═V—W=Q is CR^(U)═CR^(V)—CR^(W)═N.

In some embodiments, U is N.

In some embodiments, U is CR^(U).

In some embodiments, R^(U) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a), SR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1,2, 3, or 4 independently selected R⁸ groups.

In some embodiments, R^(U) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a), SR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R⁸ groups.

In some embodiments, R^(U) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, OR^(a), SR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d),C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b), NR^(c)C(═O)NR^(c)R^(d),NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), orS(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R⁸ groups.

In some embodiments, R^(U) is H, halo, CN, C₁₋₆ alkyl, OR^(a),C(═O)R^(b), C(═O)NR^(c)R^(d), S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d).

In some embodiments, R^(U) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,or C(═O)NR^(c)R^(d), wherein R^(c) and R^(d) are each independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, R^(U) is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆haloalkyl.

In some embodiments, R^(U) is selected from H, halo, CN, C₁₋₄ alkyl, orC₁₋₄ haloalkyl.

In some embodiments, R^(U) is H.

In some embodiments, V is N.

In some embodiments, V is CR^(V).

In some embodiments, R^(V) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a), SR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1,2, 3, or 4 independently selected R⁸ groups.

In some embodiments, R^(V) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a), SR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R⁸ groups.

In some embodiments, R^(V) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, OR^(a), SR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d),C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b), NR^(c)C(═O)NR^(c)R^(d),NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), orS(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R⁸ groups.

In some embodiments, R^(V) is H, halo, CN, C₁₋₆ alkyl, OR^(a),C(═O)R^(b), C(═O)NR^(c)R^(d), S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d).

In some embodiments, R^(V) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,or C(═O)NR^(c)R^(d), wherein R^(c) and R^(d) are each independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, R^(V) is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆haloalkyl.

In some embodiments, R^(V) is H, halo, CN, C(═O)NH₂, C₁₋₆ alkyl, or C₁₋₆haloalkyl.

In some embodiments, R^(V) is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,carbamyl, or C₁₋₄ alkylcarbamyl.

In some embodiments, R^(V) is C(═O)NR^(c)R^(d), wherein R^(c) and R^(d)are each independently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, R^(V) is C(═O)NH₂.

In some embodiments, R^(V) is H.

In some embodiments, W is N.

In some embodiments, W is CR^(W).

In some embodiments, R^(W) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a), SR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1,2, 3, or 4 independently selected R⁸ groups.

In some embodiments, R^(W) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a), SR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R⁸ groups.

In some embodiments, R^(W) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, OR^(a), SR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d),C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b), NR^(c)C(═O)NR^(c)R^(d),NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), orS(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R⁸ groups.

In some embodiments, R^(W) is H, halo, CN, C₁₋₆ alkyl, OR^(a),C(═O)R^(b), C(═O)NR^(c)R^(d), S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d).

In some embodiments, R^(W) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,or C(═O)NR^(c)R^(d), wherein R^(c) and R^(d) are each independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, R^(W) is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆haloalkyl.

In some embodiments, R^(W) is H, halo, CN, C₁₋₄ alkyl, or C₁₋₄haloalkyl.

In some embodiments, R^(W) is H.

In some embodiments, Q is N.

In some embodiments, Q is CR^(Q).

In some embodiments, R^(Q) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a), SR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1,2, 3, or 4 independently selected R⁸ groups.

In some embodiments, R^(Q) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a), SR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R⁸ groups.

In some embodiments, R^(Q) is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, OR^(a), SR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d),C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b), NR^(c)C(═O)NR^(c)R^(d),NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), orS(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R⁸ groups.

In some embodiments, R^(Q) is H, halo, CN, C₁₋₆ alkyl, OR^(a),C(═O)R^(b), C(═O)NR^(c)R^(d), S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d).

In some embodiments, R^(Q) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl,or C(═O)NR^(c)R^(d), wherein R^(c) and R^(d) are each independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, R^(Q) is H, halo, CN, C₁₋₆ alkyl, or C₁₋₆haloalkyl.

In some embodiments, R^(Q) is H.

In some embodiments, R^(Q) is H or OR^(a).

In some embodiments, R^(Q) is H or OR^(a), wherein R^(a) is selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selected R⁸groups; and each R⁸ is independently selected from OH, NO₂, CN, halo,C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments of Formula (X):

R^(Q) is selected from H, C₁₋₆ alkyl, OR^(a), and OR^(f), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selected R⁸groups;

R^(a) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R⁸ groups;

R^(f) is C₁₋₆ alkyl which is substituted with 1 substituent selectedfrom R⁹⁰ and —NHR⁸⁰;

each R⁸ is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a8), C(═O)OR^(a8), OC(═O)R^(b8), OC(═O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8), NHC(═O)NHR^(d8), NR^(c8)S(═O)₂R^(b8),and NR^(c8)C(═O)OR^(b8);

each R^(a8), R^(c8), and R^(d8) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, wherein said C₁₋₆ alkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl are each optionally substituted with 1 or 2 independentlyselected R¹⁰ groups;

each R^(b8) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 independently selected R¹⁰ groups;

-   -   each R¹⁰ is independently selected from H, halo, CN, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, OR^(a10)NR^(c10)R^(d10), and C(═O)OR^(a10),        wherein said C₁₋₆ alkyl is optionally substituted by 1 or 2        independently selected R^(G) groups;    -   each R^(a10) is independently selected from H and C₁₋₆ alkyl,        wherein said C₁₋₆ alkyl is optionally substituted with 1 or 2        independently selected R^(G) groups;

R⁸⁰ is a linear peptide chain having 2-4 amino acids; and

R⁹⁰ is a linear chain of formula —(O—C₂₋₄ alkylene)_(z)-R^(G), wherein zis 1, 2, 3, or 4.

In some embodiments, R^(Q) is H or OR^(a), wherein R^(a) is selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selected R⁸groups; and each R⁸ is independently selected from OH, NO₂, CN, halo,C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, R^(Q) is H or OR^(a), wherein R^(a) is selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1, 2,3, or 4 independently selected R⁸ groups; and each R⁸ is independentlyselected from OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments, R^(Q) is H or OR^(a), wherein R^(a) is selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1, 2,3, or 4 independently selected R⁸ groups; and each R⁸ is independentlyselected from OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.

In some embodiments, R^(Q) is H, OR^(a), halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, or C(═O)NR^(c)R^(d), wherein R^(a) is selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R⁸ groups; R^(c) and R^(d) are eachindependently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and eachR⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy,amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, R^(Q) is H or OR^(a), wherein R^(a) is selectedfrom H, C₁₋₆ alkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl areoptionally substituted by 1 group selected from CN, OH, C₁₋₃ alkyl, C₁₋₃alkoxy, carboxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-,carboxy-C₁₋₃alkoxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-, OC(═O)R^(a8), C(═O)OR^(a8),OC(═O)NHR^(d8), —NHC(═O)R^(b8), NHC(═O)NHR^(d8), C(═O)OH—C₁₋₆ alkyl-,C(═O)OH—C₁₋₆ alkoxy-C(═O)— and —NHC(═O)OR^(b)8; wherein R^(a8), R^(b8)and R^(d8) are each independently C₁₋₃ alkyl, which is optionallysubstituted by 1 or 2 groups independently selected from carboxy andamino.

In some embodiments, R^(Q) is H or OR^(a), wherein R^(a) is selectedfrom H, C₁₋₆ alkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl is optionally substituted by OH or C₁₋₃ alkoxy.

In some embodiments, R^(Q) is selected from H, methoxy,N-morpholinylpropoxy, methoxypropoxy, hydroxypropoxy,3-(4-carboxybutanamido)propoxy,3-(((2-carboxyethoxy)carbonyl)amino)propoxy,3-(((2-carboxyethyl)carbamoyl)oxy)propoxy,2-(2-(2-carboxyethoxy)ethoxy)ethoxy;2-(2-(2-(2-carboxyethoxy)ethoxy)ethoxy)ethoxy;2-(1-(3-carboxypropyl)piperidin-4-yl)ethoxy; and2-(1-((carboxymethoxy)carbonyl)piperidin-4-yl)ethoxy.

In some embodiments, R^(Q) is selected from H, methoxy,N-morpholinylpropoxy, methoxypropoxy, and hydroxypropoxy.

In some embodiments:

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selected R⁸groups;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R⁸ groups; and

each R⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments:

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selected R⁸groups;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R⁸ groups; and

each R⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, di(C₁₋₃ alkyl)aminocarbonylamino,carboxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-,carboxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkoxy-, carboxy-C₁₋₃alkoxy-carbonylamino-, carboxy-C₁₋₃ alkyl-carbonylamino-, carboxy-C₁₋₃alkyl-carbamyl-, carboxy-C₁₋₃ alkoxycarbonyl-, and carboxy-C₁₋₃ alkyl-.

In some embodiments:

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selected R⁸groups;

each R^(b) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl,wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R⁸ groups; and

each R⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,carboxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-,carboxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkoxy-, carboxy-C₁₋₃alkoxy-carbonylamino-, carboxy-C₁₋₃ alkyl-carbonylamino-, carboxy-C₁₋₃alkyl-carbamyl-, carboxy-C₁₋₃ alkoxycarbonyl-, and carboxy-C₁₋₃ alkyl-.

In some embodiments:

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selected R⁸groups;

each R^(b) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl,wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R⁸ groups; and

each R⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments:

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R⁸ groups;

each R^(b) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl,wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R⁸ groups; and

each R⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, R^(a) is H, C₁₋₄ alkyl, C₁₋₆ haloalkyl, or 4-7membered heterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₄ alkyl and 4-7membered heterocycloalkyl-C₁₋₄ alkyl, are each optionally substitutedwith 1, 2, or 3 groups independently selected from OH, NO₂, CN, halo,C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,carboxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-,carboxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkoxy-, carboxy-C₁₋₃alkoxy-carbonylamino-, carboxy-C₁₋₃ alkyl-carbonylamino-, carboxy-C₁₋₃alkyl-carbamyl-, carboxy-C₁₋₃ alkoxycarbonyl-, and carboxy-C₁₋₃ alkyl-.

In some embodiments, R^(a) is H, C₁₋₄ alkyl, C₁₋₆ haloalkyl, or 4-7membered heterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₄ alkyl and 4-7membered heterocycloalkyl-C₁₋₄ alkyl, are each optionally substitutedwith 1, 2, or 3 groups independently selected from OH, NO₂, CN, halo,C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, R^(a) is H, C₁₋₄ alkyl, or C₁₋₆ haloalkyl, whereinsaid C₁₋₄ alkyl is optionally substituted with 1, 2, or 3 groupsindependently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl,C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, R^(a) is H, C₁₋₄ alkyl, or 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein the C₁₋₄ alkyl is optionallysubstituted with OH, C₁₋₃ alkoxy, carboxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-,carboxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-C₁₋₃-alkoxy-, carboxy-C₁₋₃alkoxy-carbonylamino-, carboxy-C₁₋₃ alkyl-carbonylamino-, carboxy-C₁₋₃alkyl-carbamyl-, carboxy-C₁₋₃ alkoxycarbonyl-, and carboxy-C₁₋₃ alkyl-.

In some embodiments, R^(a) is H, C₁₋₄ alkyl, or 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein the C₁₋₄ alkyl is optionallysubstituted with OH or C₁₋₃ alkoxy.

In some embodiments, R^(a) is H or C₁₋₄ alkyl.

In some embodiments, R^(c) is H, C₁₋₄ alkyl, or C₁₋₆ haloalkyl, whereinsaid C₁₋₄ alkyl is optionally substituted with 1, 2, or 3 groupsindependently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl,C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, R^(c) is H or C₁₋₄ alkyl.

In some embodiments, R^(d) is H, C₁₋₄ alkyl, or C₁₋₆ haloalkyl, whereinsaid C₁₋₄ alkyl is optionally substituted with 1, 2, or 3 groupsindependently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl,C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, R^(d) is H or C₁₋₄ alkyl.

In some embodiments, R^(b) is C₁₋₄ alkyl, or C₁₋₆ haloalkyl, whereinsaid C₁₋₄ alkyl is optionally substituted with 1, 2, or 3 groupsindependently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl,C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, R^(b) is C₁₋₄ alkyl.

In some embodiments, R¹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R⁸ groups.

In some embodiments, R¹ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C₃₋₇cycloalkyl, wherein said C₁₋₆ alkyl or C₃₋₇ cycloalkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R⁸groups.

In some embodiments, R¹ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In some embodiments, each R⁸ is independently selected from OH, NO₂, CN,halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl,C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl,C₁₋₄ alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments, each R⁸ is independently selected from OH, NO₂, CN,halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃alkyl)amino.

In some embodiments, R¹ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C₃₋₇cycloalkyl, wherein said C₁₋₆ alkyl or C₃₋₇ cycloalkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R⁸groups.

In some embodiments, X is CR^(X); Y is CR^(Y); and Z is CR^(Z);

In some embodiments, X is N; Y is CR^(Y); and Z is CR^(Z);

In some embodiments, X is CR^(X); Y is N; and Z is CR^(Z);

In some embodiments, X is CR^(X); Y is CR^(Y); and Z is N;

In some embodiments, one of X, Y and Z are N;

In some embodiments, two of X, Y and Z are N;

In some embodiments, X is N.

In some embodiments, X is CR^(X).

In some embodiments, X is CH.

In some embodiments:

R^(X) is selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a0), SR^(a0), C(═O)R^(b0),C(═O)NR^(c0)R^(d0), C(═O)OR^(a0), OC(═O)R^(b0), OC(═O)NR^(c0)R^(d0),NR^(c0)R^(d0), NR^(c0)C(═O)R^(b0), NR^(c0)C(═O)OR^(b0),NR^(c0)(═O)NR^(c0)R^(d0), NR^(c0)S(═O)₂R^(b0),NR^(c0)S(═O)₂NR^(c0)R^(d0), S(═O)₂R^(b0), and S(═O)₂NR^(c0)R^(d0),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(G) groups;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) groups; and

each R^(b0) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, or 3 independentlyselected R^(G) groups.

In some embodiments, R^(X) is selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a0), C(═O)R^(b0),C(═O)NR^(c)R^(d), C(═O)OR^(a10), OC(═O)R^(b0), NR^(c0)R^(d0),NR^(c0)C(═O)R^(b0), NR^(c0)S(═O)₂R^(b0), S(═O)₂R^(b0), andS(═O)₂NR^(c0)R^(d0), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl, are each optionally substituted by 1, 2, 3,or 4 independently selected R^(G) groups;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(G) groups; and

each R^(b0) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R^(G) groups.

In some embodiments, R^(X) is selected from H, D, halo, CN, C₁₋₆ alkyl,and C₁₋₆ haloalkyl.

In some embodiments, R^(X) is H or C₁₋₆ alkyl.

In some embodiments, Y is N.

In some embodiments, Y is CR^(Y).

In some embodiments:

R^(Y) is selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a0), SR^(a0), C(═O)R^(b0),C(═O)NR^(c0)R^(d0), C(═O)OR^(a0), OC(═O)R^(b0), OC(═O)NR^(c0)R^(d0),NR^(c0)R^(d0), NR^(c0)C(═O)R^(b0), NR^(c0)C(═O)OR^(b0),NR^(c0)C(═O)NR^(c0)R^(d0), NR^(c0)S(═O)₂R^(b0),NR^(c0)S(═O)₂NR^(c0)R^(d0), S(═O)₂R^(b0), and S(═O)₂NR^(c0)R^(d0),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(G) groups;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) groups; and

each R^(b0) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, or 3 independentlyselected R^(G) groups.

In some embodiments, R^(X) is selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a0), C(═O)R^(b0),C(═O)NR^(c0)R^(d0), C(═O)OR^(a0), OC(═O)R^(b0), NR^(c0)R^(d0),NR^(c0)C(═O)R^(b0), NR^(c0)S(═O)₂R^(b0), S(═O)₂R^(b0), andS(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(G) groups;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(G) groups; and

each R^(b0) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R^(G) groups.

In some embodiments, R^(Y) is selected from H, D, halo, CN, C₁₋₆ alkyl,and C₁₋₆ haloalkyl.

In some embodiments, R^(Y) is selected from H, halo, and CN.

In some embodiments, Y is N, or CR^(Y), wherein R^(Y) is selected fromH, halo and CN.

In some embodiments, Y is N, CH, CF or C(CN).

In some embodiments, Y is CH, CF, or C(CN).

In some embodiments, Y is CH.

In some embodiments, Z is N.

In some embodiments, Z is CR^(Z).

In some embodiments:

R^(Z) is selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a0), SR^(a0), C(═O)R^(b0),C(═O)NR^(c0)R^(d0), C(═O)OR^(a0), OC(═O)R^(b0), OC(═O)NR^(c0)R^(d0),NR^(c0)R^(d0), NR^(c0)C(═O)R^(b0), NR^(c0)(═O)OR^(b0),NR^(c0)C(═O)NR^(c0)R^(d0), NR^(c0)S(═O)₂R^(b0),NR^(c0)S(═O)₂NR^(c0)R^(d0), S(═O)₂R^(b0), and S(═O)₂NR^(c0)R^(d0),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(G) groups;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) groups; and

each R^(b0) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, or 3 independentlyselected R^(G) groups.

In some embodiments, R^(X) is selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a0), C(═O)R^(b0),C(═O)NR^(c0)R^(d0), C(═O)OR^(a), OC(═O)R^(b0), NR^(c0)R^(d0),NR^(c0)C(═O)R^(b0), NR^(c0)S(═O)₂R^(b0), S(═O)₂R^(b0), andS(═O)₂NR^(c0)R^(d0), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl are each optionally substituted by 1, 2, 3,or 4 independently selected R^(G) groups;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(G) groups; and

each R^(b0) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R^(G) groups.

In some embodiments, R^(Z) is selected from H, D, halo, CN, C₁₋₆ alkyl,and C₁₋₆ haloalkyl.

In some embodiments, R^(Z) is selected from H, halo, and CN.

In some embodiments, R^(Z) is selected from H, F, and CN.

In some embodiments, Z is N, or CR^(Z), wherein R^(Z) is selected fromH, halo and CN.

In some embodiments, Z is N, CH, CF, or C(CN).

In some embodiments, Z is CH, CF, or C(CN).

In some embodiments, Z is CH.

In some embodiments, R³ is H or C₁₋₆ alkyl.

In some embodiments, R³ is H or methyl.

In some embodiments, R³ is H.

In some embodiments, R² is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, or 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R^(2a) groups.

In some embodiments, R² is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, orC₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ haloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(2a) groups.

In some embodiments, R² is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.

In some embodiments, R⁴ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a4), SR^(a4), C(═O)R^(b4),C(═O)NR^(c4)R^(d4), C(═O)OR^(a4), OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)OR^(b4),NR^(c4)C(═O)NR^(c4)R^(d4), NR^(c4)S(═O)₂R^(b4),NR^(c4)S(═O)₂NR^(c4)R^(d4), S(═O)₂R^(b4), or S(═O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(4a) groups.

In some embodiments, R⁴ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a4), SR^(a4), C(═O)R^(b4),C(═O)NR^(c4)R^(d4), C(═O)OR^(a4), OC(═O)R^(b4), OC(═O)NR^(C4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)OR^(b4),NR^(c4)C(═O)NR^(c4)R^(d4), NR^(c4)S(═O)₂R^(b4),NR^(c4)S(═O)₂NR^(c4)R^(d4), S(═O)₂R^(b4), or S(═O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(4a)groups.

In some embodiments:

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4a) groups; and

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(4a) groups.

In some embodiments:

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4a) groups; and

each R^(b4) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R^(4a) groups.

In some embodiments, R⁴ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or OR^(a4).

In some embodiments, R⁴ is H, C₁₋₆ alkyl, or OR^(a4).

In some embodiments of Formula (X):

R⁴ is selected from H, C₁₋₆ alkyl, OR^(a4), and OR^(f4), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selectedR^(4a) groups;

R^(a4) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R^(4a) groups;

R^(f4) is C₁₋₆ alkyl which is substituted with 1 substituent selectedfrom R⁹⁰ and —NHR⁸⁰;

each R^(4a) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a9), C(═O)OR^(a9), OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9),NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9), NHC(═O)NHR^(d9), NR^(c9)S(═O)₂R^(b9),and NR^(c9)C(═O)OR^(b9);

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, wherein said C₁₋₆ alkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl are each optionally substituted with 1 or 2 independentlyselected R¹¹ groups;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 independently selected R¹¹ groups;

each R¹¹ is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a11), NR^(c11)R^(d11), and C(═O)OR^(a11), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selectedR^(G) groups;

-   -   each R^(a11) is independently selected from H and C₁₋₆ alkyl,        wherein said C₁₋₆ alkyl is optionally substituted with 1 or 2        independently selected R^(G) groups;

each R^(c11) and R^(d11) independently selected from H and C₁₋₆ alkyl,wherein said C₁₋₆ alkyl is optionally substituted with 1 or 2independently selected R^(G) groups;

R⁸⁰ is a linear peptide chain having 2-4 amino acids; and

R⁹⁰ is a linear chain of formula —(O—C₂₋₄ alkylene)_(z)-R^(G), wherein zis 1, 2, 3, or 4.

In some embodiments, R⁴ is H, C₁₋₆ alkyl, or OR^(a4);

wherein R^(a4) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(4a) groups;

each R^(4a) is independently selected from CN, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a9), C(═O)R^(b9),C(═O)NR^(c9)R^(d9), C(═O)OR^(a9), OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9),NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9), NR^(c9)C(═O)OR^(b9),NR^(c9)C(═O)NR^(c9)R^(d9), NR^(c9)S(═O)₂R^(b9),NR^(c9)S(═O)₂NR^(c9)R^(d9), and S(═O)₂R^(b9);

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, or 3 independently selected R¹¹groups;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,each of which is optionally substituted by 1, 2, or 3 independentlyselected R¹¹ groups; and

each R¹¹ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino.

In some embodiments, R⁴ is H, C₁₋₆ alkyl, or OR^(a4);

wherein R^(a4) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R^(4a) groups;

each R^(4a) is independently selected from CN, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a9), C(═O)R^(b9), C(═O)NR^(c9)R^(d9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NR^(c9)S(═O)₂R^(b9), and NR^(c9)S(═O)₂NR^(c9)R^(d9);

each R^(a9), R^(c9), and R^(d9) independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,and 5-6 membered heteroaryl are each optionally substituted by 1 or 2independently selected R¹¹ groups;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl, each of which is optionally substituted by 1, 2, or 3independently selected R¹¹ groups; and

each R¹¹ is independently selected from C₁₋₃ alkyl and C₁₋₃ haloalkyl.

In some embodiments:

R⁴ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or OR^(a4);

R^(a4) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R^(4a) groups;

each R^(4a) is selected from CN, OR^(a9), NHR^(d9), OC(═O)R^(b9),OC(═O)NHR^(d9), NHC(═O)R^(b9), NHC(═O)OR^(b9), NHC(═O)NHR^(d9), andNHS(═O)₂R^(b9);

each R^(a9) and R^(d9) is independently selected from H and C₁₋₆ alkyloptionally substituted with 1, 2, or 3 independently selected R¹¹groups;

each R^(b9) is independently selected from C₁₋₆ alkyl and 5-6 memberedheteroaryl, each of which is optionally substituted with 1, 2, or 3independently selected R¹¹ groups; and

each R¹¹ group is independently selected from C₁₋₃ alkyl, carboxy-C₁₋₃alkoxy, carboxy, amino, and C₁₋₃ haloalkyl.

In some embodiments:

R⁴ is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or OR^(a4);

R^(a4) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R^(4a) groups;

each R^(4a) is selected from OR^(a9) and OC(═O)R^(b9);

each R^(a9) is independently selected from H and C₁₋₆ alkyl;

each R^(b9) is independently selected from 5-6 membered heteroaryl,which is optionally substituted with 1, 2, or 3 independently selectedR¹¹ groups;

-   -   and each R¹¹ group is independently selected from C₁₋₆ alkyl.

In some embodiments, R⁴ is H, C₁₋₃ alkyl, or OR^(a4), wherein R^(a4) isselected from H, C₁₋₆ alkyl, and 4-7 membered heterocycloalkyl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl and 4-7 membered heterocycloalkyl-C₁₋₄alkyl are optionally substituted by 1 group selected from CN, amino, OH,C₁₋₃ alkyl, C₁₋₃ alkoxy, carboxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-,carboxy-C₁₋₃alkoxy-C₁₋₃alkoxy-C₁₋₃-alkoxy-, OC(═O)R^(a8), C(═O)OR^(a8),OC(═O)NHR^(d8), —NHC(═O)R^(b8), NHC(═O)NHR^(d8), C(═O)OH—C₁₋₆ alkyl-,C(═O)OH—C₁₋₆ alkoxy-C(═O)— and —NHC(═O)OR^(b8); wherein R^(a8), R^(b8)and R^(d8) are each independently C₁₋₃ alkyl, which is optionallysubstituted by 1 or 2 groups independently selected from carboxy andamino; and R^(b8) is C₁₋₃ alkyl or 5-membered heteroaryl, which are eachoptionally substituted by 1 or 2 groups independently selected from C₁₋₃alkyl, carboxy and amino.

In some embodiments, R⁴ is selected from H, methyl, OH, methoxy,isopropoxy, hydroxyethoxy, hydroxypropoxy, methoxypropoxy, aminopropoxy,CN-propoxy, N-morpholinylethoxy, N-morpholinylpropoxy,(4-methylpiperazin-1-yl)propoxy,3-(((carboxymethoxy)carbonyl)amino)propoxy,3-(3-(carboxymethyl)ureido)propoxy,3-(2-amino-3-carboxypropanamido)propoxy,3-(3-carboxypropanamido)propoxy,3-(((2-carboxyethyl)carbamoyl)oxy)propoxy,2-(2-(2-carboxyethoxy)ethoxy)ethoxy,3-((3-carboxypropyl)sulfonamido)propoxy, and OCH₂CH₂CH₂OC(O)pyrazolyl,wherein the pyrazolyl is substituted by 1 or 2 C₁₋₃ alkyl groups.

In some embodiments, R⁴ is —OCH₂CH₂CH₂NH(Asp-Asp-Arg-Asp).

In some embodiments, R⁴ is selected from H, methyl, OH, methoxy,hydroxypropoxy, N-morpholinylpropoxy, and OCH₂CH₂CH₂OC(O)pyrazolyl,wherein the pyrazolyl is substituted by 1 or 2 methyl groups.

In some embodiments, R⁵ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a5), SR^(a5), C(═O)R^(b5),C(═O)NR^(c5)R^(d5), C(═O)OR^(a6), OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)OR^(b5),NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)S(═O)₂R^(b5),NR^(c5)S(═O)₂NR^(c5)R^(d5), S(═O)₂R^(b5), or S(═O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(5a) groups.

In some embodiments, R⁵ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5)C(═O)R^(b5),C(═O)NR^(c5)R^(d5), C(═O)OR^(a5), OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)OR^(b5),NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)S(═O)₂R^(b5),NR^(c5)S(═O)₂NR^(c5)R^(d5), S(═O)₂R^(b5), or S(═O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(5a)groups.

In some embodiments:

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5a) groups; and

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(5a) groups.

In some embodiments:

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5a) groups; and

each R^(b5) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R^(5a) groups.

In some embodiments, R⁵ is selected from H, halo, CN, C₁₋₄ alkyl, orC₁₋₄ haloalkyl.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a6), SR^(a6), C(═O)R^(b6),C(═O)NR^(c6)R^(d6), C(═O)OR^(a6), OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6), NR^(c6)C(═O)OR^(b6),NR^(c6)C(═O)NR^(c6)R^(d6), NR^(c6)S(═O)₂R^(b6),NR^(c6)S(═O)₂NR^(c6)R^(d6), S(═O)₂R^(b6), or S(═O)₂NR^(c6)R^(d6),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(6a) groups.

In some embodiments, R⁶ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a6), SR^(a6), C(═O)R^(b6),C(═O)NR^(c6)R^(d6), C(═O)OR^(a6), OC(═O)R^(b6), OC(═O)NR^(C6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6), NR^(c6)C(═O)OR^(b6),NR^(c6)C(═O)NR^(c6)R^(d6), NR^(c6)S(═O)₂R^(b6),NR^(c6)S(═O)₂NR^(c6)R^(d6), S(═O)₂R^(b6), or S(═O)₂NR^(c6)R^(d6),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(6a)groups.

In some embodiments, R⁶ is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl,carbamyl, and C₁₋₄ alkylcarbamyl.

In some embodiments, R⁶ is H or C(═O)NR^(c6)R^(d6).

In some embodiments, R⁶ is C(═O)NR^(c6)R^(d6).

In some embodiments, R⁶ is C(═O)NH₂.

In some embodiments:

each R^(a6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(6a) groups; and

each R^(b6) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(6a) groups.

In some embodiments:

each R^(a6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(6a) groups; and

each R^(b6) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R^(6a) groups.

In some embodiments, R⁷ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a7), SR^(a7), C(═O)R^(b7),C(═O)NR^(c7)R^(d7), C(═O)OR^(a7), OC(═O)R^(b7), OC(═O)NR^(c7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(═O)R^(b7), NR^(c7)C(═O)OR^(b7),NR^(c7)C(═O)NR^(c7)R^(d7), NR^(c7)S(═O)₂R^(b7),NR^(c7)S(═O)₂NR^(c7)R^(d7), S(═O)₂R^(b7), or S(═O)₂NR^(c7)R^(d7),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(7a)groups.

In some embodiments, R⁷ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a7), SR^(a7), C(═O)R^(b7),C(═O)NR^(c7)R^(d7), C(═O)OR^(a7), OC(═O)R^(b7), OC(═O)NR^(C7)R^(d7),NR^(c7)R^(d7), NR^(c7)C(═O)R^(b7), NR^(c7)C(═O)OR^(b7),NR^(c7)C(═O)NR^(c7)R^(d7), NR^(c7)S(═O)₂R^(b7),NR^(c7)S(═O)₂NR^(c7)R^(d7), S(═O)₂R^(b7), or S(═O)₂NR^(c7)R^(d7),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(7a)groups.

In some embodiments, R⁷ is selected from H, halo, CN, C₁₋₄ alkyl, orC₁₋₄ haloalkyl.

In some embodiments, R⁷ is H.

In some embodiments:

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(7a) groups; and

each R^(b7) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(7a) groups.

In some embodiments:

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(7a) groups; and

each R^(b7) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R⁷ groups.

In some embodiments, each R^(2a), R^(4a), R^(5a), R^(6a), and R^(7a) areindependently selected from H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₇ cycloalkyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl,4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a9), SR^(a9), C(═O)R^(b9), C(═O)NR^(c9)R^(d9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NR^(c9)C(═O)OR^(b9), NR^(c9)C(═O)NR^(c9)R^(d9), NR^(c9)S(═O)₂R^(b9),NR^(c9)S(═O)₂NR^(c9)R^(d9), S(═O)₂R^(b9), and S(═O)₂NR^(c9)R^(d9),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selected R¹¹groups.

In some embodiments, each R^(2a), R^(4a), R^(5a), R^(6a), and R^(7a) areindependently selected from H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a9), SR^(a9), C(═O)R^(b9), C(═O)NR^(c9)R^(d9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NR^(c9)C(═O)OR^(b9), NR^(c9)C(═O)NR^(c9)R^(d9), NR^(c9)S(═O)₂R^(b9),NR^(c9)S(═O)₂NR^(c9)R^(d9), S(═O)₂R^(b9), and S(═O)₂NR^(c9)R^(d9),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selected R¹¹groups.

In some embodiments, each R^(2a), R^(4a), R^(5a), R^(6a), and R^(7a) areindependently selected from H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a9), SR^(a9), C(═O)R^(b9),C(═O)NR^(c9)R^(d9), C(═O)OR^(c9), OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9),NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9), NR^(c9)C(═O)OR^(b9),NR^(c9)C(═O)NR^(c9)R^(d9), C(═NR^(e))R^(b9), NR^(c9)S(═O)₂R^(b9),NR^(c9)S(═O)₂NR^(c9)R^(d9) S(═O)₂R^(b9), and S(═O)₂NR^(c9)R^(d9),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, are eachoptionally substituted by 1, 2, 3, or 4 independently selected R¹¹groups.

In some embodiments, each R^(a9), R^(c9), and R^(d9) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl is optionally substituted with 1, 2, 3,or 4 independently selected R¹¹ groups; and

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R¹¹ groups.

In some embodiments, each R^(a9), R^(c9), and R^(d9) is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkylis optionally substituted with 1, 2, 3, or 4 independently selectedR^(U) groups; and

each R^(b9) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl are each optionally substituted with1, 2, or 3 independently selected R¹¹ groups.

In some embodiments, each R¹¹ is independently selected from OH, NO₂,CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, each R¹¹ group is independently selected from C₁₋₃alkyl, carboxy-C₁₋₃ alkoxy, carboxy, amino, and C₁₋₃ haloalkyl.

In some embodiments, each R^(2a), R^(4a), R^(5a), R^(6a), and R^(7a) areindependently selected from H, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, and di(C₁₋₆alkyl)amino.

In some embodiments, R⁵, R⁶, and R⁷ are each independently selected fromH, halo, OH, NO₂, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, R⁵, R⁶, and R⁷ are each independently selected fromH, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, carbamyl, C₁₋₆alkylcarbamyl, and di(C₁₋₆ alkyl)carbamyl.

In some embodiments, R⁵, R⁶, and R⁷ are each independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, carbamyl, C₁₋₆alkylcarbamyl, and di(C₁₋₆ alkyl)carbamyl.

In some embodiments, Ring moiety A is 5-10 membered heteroaryl, which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.

In some embodiments, Ring moiety A is 5-6 membered heteroaryl, which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.

In some embodiments, Ring moiety A is 5 membered heteroaryl, which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.

In some embodiments, Ring moiety A is a pyrazole ring, which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups.

In some embodiments, Ring moiety A is selected from1-ethyl-3-methyl-1H-pyrazol-5-yl, 3-methyl-1-propyl-1H-pyrazol-5-yl,1-ethyl-1H-pyrazol-5-yl, 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl,3-ethyl-1-methyl-1H-pyrazol-4-yl, and 1,3-dimethyl-1H-pyrazol-5-yl.

In some embodiments, each R^(A) is independently selected from halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), NR^(c1)S(═O)₂R^(b2),NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(A1) groups.

In some embodiments, each R^(A) is independently selected from halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₅cycloalkyl, OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1),C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1),C(═NR^(e))R^(b1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NR^(c1)S(═O)₂R^(b2),NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(A1)groups.

In some embodiments, each R^(A) is independently selected from halo, CN,C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(A) is independently C₁₋₆ alkyl or C₁₋₆haloalkyl.

In some embodiments, each R^(A) is independently C₁₋₆ alkyl.

In some embodiments, Ring moiety B is selected from1-ethyl-3-methyl-1H-pyrazol-5-yl, 3-methyl-1-propyl-1H-pyrazol-5-yl,1-ethyl-1H-pyrazol-5-yl, 1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl,3-ethyl-1-methyl-1H-pyrazol-4-yl, and 1,3-dimethyl-1H-pyrazol-5-yl.

In some embodiments, Ring moiety B is 1-ethyl-3-methyl-1H-pyrazol-5-yl.

In some embodiments:

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 independently selected R^(A1) groups; and

each R^(b1) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, or 3independently selected R^(A1) groups.

In some embodiments, Ring moiety B is 5-10 membered heteroaryl, which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(B)groups.

In some embodiments, Ring moiety B is 5-6 membered heteroaryl, which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(B)groups.

In some embodiments, Ring moiety B is 5 membered heteroaryl, which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(B)groups.

In some embodiments, Ring moiety B is a pyrazole ring, which isoptionally substituted by 1, 2, or 3 independently selected R^(B)groups.

In some embodiments, each R^(B) is independently selected from halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a2), SR^(a2), C(═O)R^(b2), C(═O)NR^(c2)R^(d2), C(═O)OR^(a2),OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2),NR^(c2)C(═O)OR^(b2), NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)₂R^(b2), and S(═O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(B1) groups.

In some embodiments, each R^(B) is independently selected from halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a2),SR^(a), C(═O)R^(b2), C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2),OC(═O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2),NR^(c2)C(═O)OR^(b2), NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)₂R^(b2), and S(═O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(B1)groups.

In some embodiments, each R^(B) is independently selected from halo, CN,C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, each R^(B) is independently C₁₋₆ alkyl or C₁₋₆haloalkyl.

In some embodiments, each R^(B) is independently C₁₋₆ alkyl.

In some embodiments:

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, or 3 independently selected R^(B1) groups; and

each R^(b2) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted with 1, 2, or 3independently selected R^(B1) groups.

In some embodiments, each R^(A1) and R^(B1) is independently selectedfrom H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, OR^(a12), SR^(a12), C(═O)R^(b12), C(═O)NR^(c12)R^(d12),C(═O)OR^(a12), OC(═O)R^(b12), OC(═O)NR^(c12)R^(d12), NR^(c12)R^(d12),NR^(c12)C(═O)R^(b12) NR^(c12)C(═O)OR^(b12),NR^(c12)C(═O)NR^(c12)R^(d12), NR^(c12)S(═O)₂R^(b12),NR^(c12)S(═O)₂NR^(c12)R^(d12), S(═O)₂R^(b12) and S(═O)₂NR^(c12)R^(d12),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(G)groups.

In some embodiments:

each R^(a12), R^(c12), and R^(d12) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(G) groups; and

each R^(b12) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R^(G) groups.

In some embodiments, each R^(A1) and R^(B1) is independently selectedfrom H, halo, CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, L¹, L², and L³ are each independently selected from-R-R-, -R-R-R-, -Cy-, -R-Cy-, -Cy-R-, and -R-Cy-R-.

In some embodiments, L¹, L², and L³ are each independently selected from-R-R-, -R-R-R-, -Cy-, -R-Cy-, and -Cy-R-.

In some embodiments, L¹, L², and L³ are each independently selected from-R-R- and -R-R-R-.

In some embodiments, L¹ is -R-R-R-.

In some embodiments, L¹ is -R-R-.

In some embodiments, L² is -R-R-R-.

In some embodiments, L² is -R-R-.

In some embodiments, L³ is -R-R-R-.

In some embodiments, L³ is -R-R-.

In some embodiments, R is M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, C₁₋₆ alkylene-M, or M-C₁₋₆ alkylene.

In some embodiments, each R is independently M, C₁₋₆ alkylene, C₂₋₆alkenylene, or C₂₋₆ alkynylene.

In some embodiments, each R is independently M, C₁₋₃ alkylene, C₂₋₃alkenylene, or C₂₋₃ alkynylene.

In some embodiments, each R is independently C₁₋₆ alkylene or C₂₋₆alkenylene.

In some embodiments, each R is independently C₁₋₃ alkylene or C₂₋₃alkenylene.

In some embodiments, each M is independently —O—, —C(O)—, —C(O)NR^(L)—,—OC(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—, —NR^(L)S(O)₂₋,—S(O)₂—, or —S(O)₂NR^(L)—, provided that when M is attached to anitrogen atom, then M is selected from —C(O)—, —C(O)NR^(L)—, —C(O)O—,—S(O)₂—, or —S(O)₂NR^(L)—; and each R^(L) is independently selected fromH and C₁₋₃ alkyl.

In some embodiments, L¹ is —CH₂—CH═CH—CH₂—.

In some embodiments, L² is —CH₂—CH═CH—CH₂—.

In some embodiments, L³ is —CH₂—CH═CH—CH₂—.

In some embodiments:

U is N or CR^(U);

V is N or CRY;

W is N or CR^(W);

Q is N or CR^(Q);

wherein U═V—W=Q is selected from CR^(U)═CR^(V)—CR^(W)═CR^(Q),N═CR^(V)—CR^(W)═CR^(Q), CR^(U)═N—CR^(W)═CR^(Q), CR^(U)═CR^(V)—N═CR^(Q),CR^(U)═CR^(V)—CR^(W)═N, N═N—CR^(W)═CR^(Q), CR^(U)═N—N═CR^(Q),CR^(U)═CR^(V)—N═N, N═CR^(V)—CR^(W)═N, N═CR^(V)—N═CR^(Q),CR^(U)═N—CR^(W)═N, N═N—CR^(W)═N, and N═CR^(V)—N═N;

R^(U), R^(V), R^(W), and R^(Q) are each independently selected from H,D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a), SR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a),OC(═O)R^(b), OC(═O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(═O)R^(b),NR^(c)C(═O)OR^(b), NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b),NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), and S(═O)₂NR^(c)R^(d), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1,2, 3, or 4 independently selected R⁸ groups;

each R⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR¹⁰ groups;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R¹⁰ groups;

each R¹⁰ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

X is N or CR^(X);

Y is N or CR^(Y);

Z is N or CR^(Z);

wherein i) X, Y and Z are CR^(X), CR^(Y), and CR^(Z) respectively, orii) only one of X, Y and Z is N, or iii) only two of X, Y and Z are N;

R^(X), R^(Y), and R^(Z) are each independently selected from H, D, halo,CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a0), SR^(a10), C(═O)R^(b0), C(═O)NR^(c0)R^(d0), C(═O)OR^(a0),OC(═O)R^(b0), OC(═O)NR^(c0)R^(d0), NR^(c0)R^(d0), NR^(c0)C(═O)R^(b0),NR^(c0)C(═O)OR^(b0), NR^(c0)C(═O)NR^(c0)R^(d0), NR^(c0)S(═O)₂R^(b0),NR^(c0)S(═O)₂NR^(c0)R^(d0), S(═O)₂R^(b), and S(═O)₂NR^(c0)R^(d0),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(G) groups;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) groups;

each R^(b0) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, or 3 independentlyselected R^(G) groups;

R¹ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R² is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R³ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R⁴ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4), C(═O)OR^(a4),OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(═O)R^(b4),NR^(c4)C(═O)OR^(b4), NR^(c4)C(═O)NR^(c4)R^(d4), NR^(c4)S(═O)₂R^(b4),NR^(c4)S(═O)₂NR^(c4)R^(d4), S(═O)₂R^(b4), or S(═O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(4a) groups;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4a) groups;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(4a) groups;

R⁵ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5), C(═O)OR^(a5),OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5),NR^(c5)C(═O)OR^(b5), NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)S(═O)₂R^(b5),NR^(c5)S(═O)₂NR^(c5)R^(d5), S(═O)₂R^(b5), or S(═O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(5a) groups;

-   -   each R^(a5), R^(c5), and R^(d5) is independently selected from        H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇        cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered        heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7        membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered        heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered        heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄        alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄        alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl are each        optionally substituted with 1, 2, 3, or 4 independently selected        R^(5a) groups;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(5a) groups;

R⁶ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a6), SR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6), C(═O)OR^(a6),OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6),NR^(c6)C(═O)OR^(b6), NR^(c6)C(═O)NR^(c6)R^(d6), NR^(c6)S(═O)₂R^(b6),NR^(c6)S(═O)₂NR^(c6)R^(d6), S(═O)₂R^(b6), or S(═O)₂NR^(c6)R^(d6),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(6a) groups;

each R^(a6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(6a) groups;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(6a) groups;

R⁷ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a7), SR^(a7), C(═O)R^(b7), C(═O)NR^(c7)R^(d7), C(═O)OR^(a7),OC(═O)R^(b7), OC(═O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(═O)R^(b7),NR^(c7)C(═O)OR^(b7), NR^(c7)C(═O)NR^(c7)R^(d7), NR^(c7)S(═O)₂R^(b7),NR^(c7)S(═O)₂NR^(c7)R^(d7), S(═O)₂R^(b7), or S(═O)₂NR^(c7)R^(d7),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R⁷groups;

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(7a) groups;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(7a) groups;

R^(4a), R^(5a), R^(6a), and R^(7a) are independently selected from H,halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a9), SR^(a9), C(═O)R^(b9), C(═O)NR^(c9)R^(d9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NR^(c9)C(═O)OR^(b9), NR^(c9)C(═O)NR^(c9)R^(d9), C(═NR^(e))R^(b9),NR^(c9)S(═O)₂R^(b9), NR^(c9)S(═O)₂NR^(c9)R^(d9), S(═O)₂R^(b9), andS(═O)₂NR^(c9)R^(d9), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, are each optionally substituted by 1, 2, 3, or 4 independentlyselected R¹¹ groups;

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl is optionally substituted with 1, 2, 3,or 4 independently selected R¹¹ groups;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

each R¹¹ is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino;

Ring moiety A is selected from C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl, and 5-10 membered heteroaryl, each of whichis optionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

Ring moiety B is selected from C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl, and 5-10 membered heteroaryl, each of whichis optionally substituted by 1, 2, 3, or 4 independently selected R^(B)groups;

each R^(A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a1), SR^(a1), C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)OR^(b1),NR^(c1)C(═O)NR^(c1)R^(d1), NR^(c1)S(═O)₂R^(b2),NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(A1) groups.

each R^(B) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), C(═O)R^(b2),C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)₂R^(b2), and S(═O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(B1) groups;

each R^(A1) and R^(B1) is independently selected from H, halo, CN, NO₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a12),SR^(a12), C(═O)R^(b12), C(═O)NR^(c12)R^(d12), C(═O)OR^(a12),OC(═O)R^(b12), OC(═O)NR^(c12)R^(d12), NR^(c12)R^(d12),NR^(c12)C(═O)R^(b12), NR^(c12)C(═O)OR^(b12),NR^(c12)C(═O)NR^(c12)R^(d12), NR^(c12)S(═O)₂R^(b12),NR^(c12)S(═O)₂NR^(c12)R^(d12), S(═O)₂R^(b12), and S(═O)₂NR^(c12)R^(d12),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(G)groups;

each R^(a12), R^(c12), and R^(d12) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(G) groups;

each R^(b12) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R^(G) groups;

-   -   n is 0 or 1;    -   m is 0 or 1;    -   s is 0 or 1;

wherein n+m+s=1 or 2;

-   -   when n is 1, R¹ and R² taken together form a linking group L¹;    -   when m is 1, one of R^(A) and one of R^(B) taken together form a        linking group L²;    -   when s is 1, R^(Q) and R⁴ taken together form a linking group        L³;

L¹, L², and L³ are each independently selected from -R-R-, -R-R-R-,-Cy-, -R-Cy-, -Cy-R-, and -R-Cy-R-;

each R is independently M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, C₁₋₆ alkylene-M, or M-C₁₋₆ alkylene, wherein each of saidC₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is optionallysubstituted by 1, 2, 3, or 4 groups independently selected R^(G) groups;

each Cy is independently selected from C₃₋₁₄ cycloalkyl, phenyl, 4-14membered heterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(G)groups;

each M is independently —O—, —S—, —C(O)—, —C(O)NR^(L)—, —C(O)O—,—OC(O)—, —OC(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—,—NR^(L)C(O)NR^(L)—, —NR^(L)S(O)₂₋, —S(O)₂—, —S(O)₂NR^(L)—, or—NR^(L)S(O)₂NR^(L)—; provided that when M is attached to a nitrogenatom, then M is selected from —C(O)—, —C(O)NR^(L)—, —C(O)O—, —S(O)₂—, or—S(O)₂NR^(L)—;

each R^(L) is independently H or C₁₋₃ alkyl; and

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments:

U is N or CR^(U);

V is N or CR^(V);

W is N or CR^(W);

Q is N or CR^(Q);

wherein U═V—W=Q is selected from CR^(U)═CR^(V)—CR^(W)═CR^(Q),N═CR^(V)—CR^(W)═CR^(Q), CR^(U)═N—CR^(W)═CR^(Q), CR^(U)═CR^(V)—N═CR^(Q),CR^(U)═CR^(V)—CR^(W)═N, N═N—CR^(W)═CR^(Q), CR^(U)═N—N═CR^(Q),CR^(U)═CR^(V)—N═N, N═CR^(V)—CR^(W)═N, N═CR^(V)—N═CR^(Q),CR^(U)═N—CR^(W)═N, N═N—CR^(W)═N, and N═CR^(V)—N═N;

R^(U), R^(V), R^(W), and R^(Q) are each independently selected from H,D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a), SR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a),OC(═O)R^(b), OC(═O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(═O)R^(b),NR^(c)C(═O)OR^(b), NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b),NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), and S(═O)₂NR^(c)R^(d), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1,2, 3, or 4 independently selected R⁸ groups;

each R⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selected R⁸groups;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R⁸ groups;

each R^(e) is independently selected from H, CN, OH, C₁₋₄ alkyl, andC₁₋₄ alkoxy;

X is N or CR^(X);

Y is N or CRY;

Z is N or CR^(Z);

wherein i) X, Y and Z are CR^(X), CR^(Y), and CR^(Z) respectively, orii) only one of X, Y and Z is N, or iii) only two of X, Y and Z are N;

R^(X), R^(Y), and R^(Z) are each independently selected from H, D, halo,CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a0), C(═O)R^(b0), C(═O)NR^(c0)R^(d0), C(═O)OR^(a10), OC(═O)R^(b0),NR^(c0)R^(d0), NR^(c0)C(═O)R^(b0), NR^(c0)S(═O)₂R^(b0), S(═O)₂R^(b0),and S(═O)₂NR^(c0)R^(d0), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl are each optionally substituted by 1, 2, 3,or 4 independently selected R^(G) groups;

each R^(a0), R^(c0), and R^(d0) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl are each optionallysubstituted with 1, 2, 3, or 4 independently selected R^(G) groups;

each R^(b0) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R^(G) groups.

R¹ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R² is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R³ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R⁴ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4), C(═O)OR^(a4),OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(═O)R^(b4),NR^(c4)C(═O)OR^(b4), NR^(c4)C(═O)NR^(c4)R^(d4), NR^(c4)S(═O)₂R^(b4),NR^(c4)S(═O)₂NR^(c4)R^(d4), S(═O)₂R^(b4), or S(═O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(4a) groups;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4a) groups;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(4a) groups;

R⁵ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5), C(═O)OR^(a5),OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5),NR^(c5)C(═O)OR^(b5), NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)S(═O)₂R^(b5),NR^(c5)S(═O)₂NR^(c5)R^(d5), S(═O)₂R^(b5), or S(═O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(5a) groups;

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5a) groups;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(5a) groups;

R⁶ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a6), SR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6), C(═O)OR^(a6),OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6),NR^(c6)C(═O)OR^(b6), NR^(c6)C(═O)NR^(c6)R^(d6), NR^(c6)S(═O)₂R^(b6),NR^(c6)S(═O)₂NR^(c6)R^(d6), S(═O)₂R^(b6), or S(═O)₂NR^(c6)R^(d6),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(6a) groups;

each R^(a6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(6a) groups;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(6a) groups;

R⁷ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a7), SR^(a7), C(═O)R^(b7), C(═O)NR^(c7)R^(d7), C(═O)OR^(a7),OC(═O)R^(b7), OC(═O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(═O)R^(b7),NR^(c7)C(═O)OR^(b7), NR^(c7)C(═O)NR^(c7)R^(d7), NR^(c7)S(═O)₂R^(b7),NR^(c7)S(═O)₂NR^(c7)R^(d7), S(═O)₂R^(b7), or S(═O)₂NR^(c7)R^(d7),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(7a)groups;

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(7a) groups;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(7a) groups;

R^(4a), R^(5a), R^(6a), and R^(7a) are independently selected from H,halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a9), SR^(a9), C(═O)R^(b9), C(═O)NR^(c9)R^(d9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NR^(c9)C(═O)OR^(b9), NR^(c9)C(═O)NR^(c9)R^(d9), C(═NR^(e))R^(b9),NR^(c9)S(═O)₂R^(b9), NR^(c9)S(═O)₂NR^(c9)R^(d9), S(═O)₂R^(b9), andS(═O)₂NR^(c9)R^(d9), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, are each optionally substituted by 1, 2, 3, or 4 independentlyselected R¹¹ groups;

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl is optionally substituted with 1, 2, 3,or 4 independently selected R¹¹ groups;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

each R¹¹ is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino;

Ring moiety A is selected from C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

Ring moiety B is selected from C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(B)groups;

each R^(A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a1), SR^(a1), C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)OR^(b1),NR^(c1)C(═O)NR^(c1)R^(d1), NR^(c1)S(═O)₂R^(b2),NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(A1) groups;

each R^(B) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), C(═O)R^(b2),C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)₂R^(b2), and S(═O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(B1) groups;

each R^(A1) and R^(B1) is independently selected from H, halo, CN, NO₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a12),SR^(a12), C(═O)R^(b12), C(═O)NR^(c12)R^(d12), C(═O)OR^(a12)OC(═O)R^(b12), OC(═O)NR^(c12)R^(d12), NR^(c12)R^(d12),NR^(c12)C(═O)R^(b12), NR^(c12)C(═O)OR^(b12)NR^(c12)C(═O)NR^(c12)R^(d12), NR^(c12)S(═O)₂R^(b12),NR^(c12)S(═O)₂NR^(c12)R^(d12), S(═O)₂R^(b12), and S(═O)₂NR^(c12)R^(d12),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(G)groups;

each R^(a12), R^(c12), and R^(d12) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(G) groups;

each R^(b12) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R^(G) groups;

-   -   n is 0 or 1;    -   m is 0 or 1;    -   s is 0 or 1;

wherein n+m+s=1 or 2;

-   -   when n is 1, R¹ and R² taken together form a linking group L¹;    -   when m is 1, one of R^(A) and one of R^(B) taken together form a        linking group L²;    -   when s is 1, R^(Q) and R⁴ taken together form a linking group        L³;

L¹, L², and L³ are each independently selected from -R-R-, -R-R-R-,-Cy-, -R-Cy-, -Cy-R-, and -R-Cy-R-;

-   -   each R is independently M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆        alkynylene, C₁₋₆ alkylene-M, or M-C₁₋₆ alkylene, wherein each of        said C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is        optionally substituted by 1, 2, 3, or 4 groups independently        selected R^(G) groups;

each Cy is independently selected from C₃₋₁₄ cycloalkyl, phenyl, 4-14membered heterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(G)groups;

each M is independently —O—, —S—, —C(O)—, —C(O)NR^(L)—, —C(O)O—,—OC(O)—, —OC(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—,—NR^(L)C(O)NR^(L)—, —NR^(L)S(O)₂₋, —S(O)₂—, —S(O)₂NR^(L)—, or—NR^(L)S(O)₂NR^(L)—; provided that when M is attached to a nitrogenatom, then M is selected from —C(O)—, —C(O)NR^(L)—, —C(O)O—, —S(O)₂—, or—S(O)₂NR^(L)—;

each R^(L) is independently H or C₁₋₃ alkyl; and

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments:

U is N or CR^(U);

V is N or CR^(V);

W is N or CR^(W);

Q is N or CR^(Q);

wherein U═V—W=Q is selected from CR^(U)═CR^(V)—CR^(W)═CR^(Q),N═CR^(V)—CR^(W)═CR^(Q), CR^(U)═N—CR^(W)═CR^(Q), CR^(U)═CR^(V)—N═CR^(Q),CR^(U)═CR^(V)—CR^(W)═N, N═N—CR^(W)═CR^(Q), CR^(U)═N—N═CR^(Q),CR^(U)═CR^(V)—N═N, N═CR^(V)—CR^(W)═N, N═CR^(V)—N═CR^(Q),CR^(U)═N—CR^(W)═N, N═N—CR^(W)═N, and N═CR^(V)—N═N;

R^(U), R^(V), R^(W), and R^(Q) are each independently selected from H,D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a), SR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a),OC(═O)R^(b), OC(═O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(═O)R^(b),NR^(c)C(═O)OR^(b), NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b),NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), and S(═O)₂NR^(c)R^(d), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2,3, or 4 independently selected R⁸ groups;

each R⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR¹⁰ groups;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R¹⁰ groups;

each R¹⁰ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

X is N or CR^(X);

Y is N or CR^(Y);

Z is N or CR^(Z);

wherein i) X, Y and Z are CR^(X), CR^(Y), and CR^(Z) respectively, orii) only one of X, Y and Z is N, or iii) only two of X, Y and Z are N;

R^(X), R^(Y), and R^(Z) are each independently selected from H, D, halo,CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R¹ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R² is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R³ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R⁴ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4), C(═O)OR^(a4),OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(═O)R^(b4),NR^(c4)C(═O)OR^(b4), NR^(c4)C(═O)NR^(c4)R^(d4), NR^(c4)S(═O)₂R^(b4),NR^(c4)S(═O)₂NR^(c4)R^(d4), S(═O)₂R^(b4), or S(═O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(4a) groups;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(4a) groups;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(4a) groups;

R⁵ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5), C(═O)OR^(a),OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5),NR^(c5)C(═O)OR^(b5), NR^(c5)C(═O)NR^(c8)R^(d8), NR^(c5)S(═O)₂R^(b5),NR^(c5)S(═O)₂NR^(c5)R^(d5), S(═O)₂R^(b5), or S(═O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(5a) groups;

each R^(a5), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(5a) groups;

each R^(b5) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(5a) groups;

R⁶ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a6), SR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6), C(═O)OR^(a6),OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6),NR^(c6)C(═O)OR^(b6), NR^(c6)C(═O)NR^(c6)R^(d6), NR^(c6)S(═O)₂R^(b6),NR^(c6)S(═O)₂NR^(c6)R^(d6), S(═O)₂R^(b6), or S(═O)₂NR^(c6)R^(d6),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(6a) groups;

each R^(a6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(6a) groups;

each R^(b6) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(6a) groups;

R⁷ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a7), SR^(a7), C(═O)R^(b7), C(═O)NR^(c7)R^(d7), C(═O)OR^(a7),OC(═O)R^(b7), OC(═O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(═O)R^(b7),NR^(c7)C(═O)OR^(b7), NR^(c7)C(═O)NR^(c7)R^(d7), NR^(c7)S(═O)₂R^(b7),NR^(c7)S(═O)₂NR^(c7)R^(d7), S(═O)₂R^(b7), or S(═O)₂NR^(c7)R^(d7),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(7a)groups;

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(7a) groups;

each R^(b7) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(7a) groups;

R^(4a), R^(5a), R^(6a), and R^(7a) are independently selected from H,halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a9), SR^(a9), C(═O)R^(b9), C(═O)NR^(c9)R^(d9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NR^(c9)C(═O)OR^(b9), NR^(c9)C(═O)NR^(c9)R^(d9), C(═NR^(e))R^(b9),NR^(c9)S(═O)₂R^(b9), NR^(c9)S(═O)₂NR^(c9)R^(d9), S(═O)₂R^(b9), andS(═O)₂NR^(c9)R^(d9), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, are each optionally substituted by 1, 2, 3, or 4 independentlyselected R¹¹ groups;

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl is optionally substituted with 1, 2, 3,or 4 independently selected R¹¹ groups;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R¹¹ groups;

each R¹¹ is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino;

Ring moiety A is selected from C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups;

Ring moiety B is selected from C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(B)groups;

each R^(A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a1), SR^(a1), C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)OR^(b1),NR^(c1)C(═O)NR^(c1)R^(d1), NR^(c1)S(═O)₂R^(b2),NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(A1) groups;

each R^(B) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a2), SR^(a2), C(═O)R^(b2),C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)₂R^(b2), and S(═O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(B1) groups;

each R^(A1) and R^(B1) is independently selected from H, halo, CN, NO₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a12),SR^(a12), C(═O)R^(b11)2, C(═O)NR^(c12)R^(d12), C(═O)OR^(a12)OC(═O)R^(b12), OC(═O)NR^(c12)R^(d12), NR^(c12)R^(d12),NR^(c12)C(═O)R^(b12), NR^(c12)C(═O)OR^(b12)NR^(c12)C(═O)NR^(c12)R^(d12), NR^(c12)S(═O)₂R^(b12),NR^(c12)S(═O)₂NR^(c12)R^(d12), S(═O)₂R^(b12), and S(═O)₂NR^(c12)R^(d12),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(G)groups;

each R^(a12), R^(c12), and R^(d12) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(G) groups;

each R^(b12) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R^(G) groups;

n is 0 or 1;

m is 0 or 1;

s is 0 or 1;

wherein n+m+s=1 or 2;

when n is 1, R¹ and R² taken together form a linking group L¹;

when m is 1, one of R^(A) and one of R^(B) taken together form a linkinggroup L²;

when s is 1, R^(Q) and R⁴ taken together form a linking group L³;

L¹, L², and L³ are each independently selected from -R-R-, -R-R-R-,-Cy-, -R-Cy-, -Cy-R-, and -R-Cy-R-;

each R is independently M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, C₁₋₆ alkylene-M, or M-C₁₋₆ alkylene, wherein each of saidC₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is optionallysubstituted by 1, 2, 3, or 4 groups independently selected R^(G) groups;

each Cy is independently selected from C₃₋₁₄ cycloalkyl, phenyl, 4-14membered heterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(G)groups;

each M is independently —O—, —S—, —C(O)—, —C(O)NR^(L)—, —C(O)O—,—OC(O)—, —OC(O)NR^(L)—, —NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—,—NR^(L)C(O)NR^(L)—, —NR^(L)S(O)₂₋, —S(O)₂—, —S(O)₂NR^(L)—, or—NR^(L)S(O)₂NR^(L)—; provided that when M is attached to a nitrogenatom, then M is selected from —C(O)—, —C(O)NR^(L)—, —C(O)O—, —S(O)₂—, or—S(O)₂NR^(L)—;

each R^(L) is independently H or C₁₋₃ alkyl; and

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments:

U is N or CR^(U);

V is N or CR^(V);

W is N or CR^(W);

Q is N or CR^(Q);

wherein U═V—W=Q is selected from CR^(U)═CR^(V)—CR^(W)═CR^(Q),N═CR^(V)—CR^(W)═CR^(Q), CR^(U)═N—CR^(W)═CR^(Q), CR^(U)═CR^(V)—N═CR^(Q),CR^(U)═CR^(V)—CR^(W)═N, N═N—CR^(W)═CR^(Q), CR^(U)═N—N═CR^(Q),CR^(U)═CR^(V)—N═N, N═CR^(V)—CR^(W)═N, N═CR^(V)—N═CR^(Q),CR^(U)═N—CR^(W)═N, N═N—CR^(W)═N, and N═CR^(V)—N═N;

R^(U), R^(V), R^(W), and R^(Q) are each independently selected from H,D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a),SR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b),OC(═O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are each optionallysubstituted by 1, 2, 3, or 4 independently selected R⁸ groups;

each R⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R¹⁰ groups;

each R^(b) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl,wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3independently selected R¹⁰ groups; and

each R¹⁰ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino;

X is N or CR^(X);

Y is N or CR^(Y);

Z is N or CR^(Z);

wherein i) X, Y and Z are CR^(X), CR^(Y), and CR^(Z) respectively, orii) only one of X, Y and Z is N, or iii) only two of X, Y and Z are N;

R^(X), R^(Y), and R^(Z) are each independently selected from H, D, halo,CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R¹ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R² is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R³ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R⁴ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, OR^(a4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4),C(═O)OR^(a4), OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)OR^(b4), NR^(c4)C(═O)NR^(c4)R^(d4),NR^(c4)S(═O)₂R^(b4), NR^(c4)S(═O)₂NR^(c4)R^(d4) S(═O)₂R^(b4), orS(═O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(4a) groups;

each R^(a4), R^(c4), and R^(d4) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(4a) groups;

each R^(b4) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R^(4a) groups;

each R^(a), R^(c5), and R^(d5) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(5a) groups;

each R^(b5) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R^(5a) groups;

R⁶ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, OR^(a6), SR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6),C(═O)OR^(a6), OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6)NR^(c6)C(═O)R^(b6), NR^(c6)C(═O)OR^(b6), NR^(c6)C(═O)NR^(c6)R^(d6),NR^(c6)S(═O)₂R^(b6), NR^(c6)S(═O)₂NR^(c6)R^(d6) S(═O)₂R^(b6), orS(═O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(6a) groups;

each R^(a6), R^(c6), and R^(d6) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(6a) groups;

each R^(b6) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R^(6a) groups;

R⁷ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, OR^(a7), SR^(a7), C(═O)R^(b7), C(═O)NR^(c7)R^(d7),C(═O)OR^(a7), OC(═O)R^(b7), OC(═O)NR^(c7)R^(d7), NR^(c7)R^(d7),NR^(c7)C(═O)R^(b7), NR^(c7)C(═O)OR^(b7), NR^(c7)C(═O)NR^(c7)R^(d7),NR^(c7)S(═O)₂R^(b7), NR^(c7)S(═O)₂NR^(c7)R^(d7)S(═O)₂R^(b7), orS(═O)₂NR^(c7)R^(d7), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(7a) groups;

each R^(a7), R^(c7), and R^(d7) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(7a) groups;

each R^(b7) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R^(7a) groups;

R^(4a), R^(5a), R^(6a), and R^(7a) are independently selected from H,halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a9), SR^(a9), C(═O)R^(b9), C(═O)NR^(c9)R^(d9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NR^(c9)C(═O)OR^(b9), NR^(c9)C(═O)NR^(c9)R^(d9), C(═NR^(e))R^(b9),NR^(c9)S(═O)₂R^(b9), NR^(c9)S(═O)₂NR^(c9)R^(d9), S(═O)₂R^(b9), andS(═O)₂NR^(c9)R^(d9), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, are each optionally substituted by 1, 2, 3, or 4 independentlyselected R¹¹ groups;

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R¹¹ groups;

each R^(b9) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl are each optionally substituted with1, 2, or 3 independently selected R¹¹ groups;

each R¹¹ is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino;

Ring moiety A is selected from phenyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl, each of which is optionally substituted by1, 2, 3, or 4 independently selected R^(A) groups;

Ring moiety B is selected from phenyl, 4-6 membered heterocycloalkyl,and 5-6 membered heteroaryl, each of which is optionally substituted by1, 2, 3, or 4 independently selected R^(B) groups;

each R^(A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl, OR^(a1),SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1),NR^(c1)S(═O)₂R^(b2), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), andS(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(A1) groups;

each R^(B) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl, OR^(a1),SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1),NR^(c1)S(═O)₂R^(b2), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), andS(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(B1) groups;

each R^(a12), R^(c12), and R^(d12) is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(G) groups;

each R^(b12) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R^(G) groups; each R^(A1) and R^(B1) isindependently selected from H, halo, CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

n is 0 or 1;

m is 0 or 1;

s is 0 or 1;

wherein n+m+s=1 or 2;

when n is 1, R¹ and R² taken together form a linking group L¹;

when m is 1, one of R^(A) and one of R^(B) taken together form a linkinggroup L²;

when s is 1, R^(Q) and R⁴ taken together form a linking group L³; L¹,L², and L³ are each independently selected from -R-R-, -R-R-R-, -Cy-,-R-Cy-, -Cy-R-, and -R-Cy-R-;

each R is independently M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, C₁₋₆ alkylene-M, or M-C₁₋₆ alkylene, wherein each of saidC₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene is optionallysubstituted by 1, 2, 3, or 4 groups independently selected R^(G) groups;

each Cy is independently selected from C₃₋₁₄ cycloalkyl, phenyl, 4-14membered heterocycloalkyl, and 5-6 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(G)groups;

each M is independently —O—, —C(O)—, —C(O)NR^(L)—, —OC(O)NR^(L)—,—NR^(L)—, —NR^(L)C(O)—, —NR^(L)C(O)O—, —NR^(L)S(O)₂₋, —S(O)₂—, or—S(O)₂NR^(L)—, provided that when M is attached to a nitrogen atom, thenM is selected from —C(O)—, —C(O)NR^(L)—, —C(O)O—, —S(O)₂—, or—S(O)₂NR^(L)—;

each R^(L) is independently selected from H and C₁₋₃ alkyl; and

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments:

U is CR^(U);

V is CR^(V);

W is CR^(W);

Q is CR^(Q);

R^(U) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C(═O)NR^(c)R^(d);

R^(V) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C(═O)NR^(c)R^(d);

R^(W) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C(═O)NR^(c)R^(d);

R^(Q) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C(═O)NR^(c)R^(d);

each R^(c) and R^(d) is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl;

X is CR^(X);

R^(X) is selected from H, D, halo, CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

Y is N;

Z is N;

R¹ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl;

R², R⁴, R⁵, R⁶, and R⁷ are each independently selected from H, halo, CN,OH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, carbamyl, C₁₋₆ alkylcarbamyl, anddi(C₁₋₆ alkyl)carbamyl;

R³ is H;

Ring moiety A is a pyrazole ring, which is optionally substituted by 1,2, or 3 independently selected R^(A) groups;

Ring moiety B is a pyrazole ring, which is optionally substituted by 1,2, or 3 independently selected R^(B) groups;

each R^(A) is independently selected from halo, CN, C₁₋₆ alkyl, and C₁₋₆haloalkyl;

each R^(B) is independently selected from halo, CN, C₁₋₆ alkyl, and C₁₋₆haloalkyl;

n is 0 or 1;

m is 0 or 1;

s is 0 or 1;

wherein n+m+s=1 or 2;

when n is 1, R¹ and R² taken together form a linking group L¹;

when m is 1, one of R^(A) and one of R^(B) taken together form a linkinggroup L²;

when s is 1, R^(Q) and R⁴ taken together form a linking group L³;

L¹ is —CH₂—CH═CH—CH₂—;

L² is —CH₂—CH═CH—CH₂—; and

L³ is —CH₂—CH═CH—CH₂—.

In some embodiments:

U is CR^(U);

V is CR^(V);

W is CR^(W);

Q is CR^(Q);

R^(U) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, or C(═O)NR^(c)R^(d);

R^(V) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, or C(═O)NR^(c)R^(d);

R^(W) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, or C(═O)NR^(c)R^(d);

R^(Q) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a), orC(═O)NR^(c)R^(d);

R^(a) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R⁸ groups;

each R⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino;

each R^(c) and R^(d) is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl;

X is CR^(X);

Y is CR^(Y) or N;

Z is CR^(Z) or N;

R^(X) is selected from H, D, halo, CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R³ is H;

R⁵, R⁶, and R⁷ are each independently selected from H, halo, CN, OH,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, carbamyl, C₁₋₆ alkylcarbamyl, anddi(C₁₋₆ alkyl)carbamyl;

R⁴ is H, C₁₋₆ alkyl, or OR^(a4);

R^(a4) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R^(4a) groups;

each R^(4a) is independently selected from CN, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a9), C(═O)R^(b9),C(═O)NR^(c9)R^(d9), C(═O)OR^(a9), OC(═O)R^(b9), OC(═O)NR^(C9)R^(d9),NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9), NR^(c9)C(═O)OR^(b9),NR^(c9)C(═O)NR^(c9)R^(d9), NR^(c9)S(═O)₂R^(b9),NR^(c9)S(═O)₂NR^(c9)R^(d9), and S(═O)₂R^(b9);

each R^(a9), R^(c9), and R^(d9) independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,and 5-6 membered heteroaryl are each optionally substituted by 1 or 2independently selected R¹¹ groups;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl, each of which is optionally substituted by 1, 2, or 3independently selected R¹¹ groups;

each R¹¹ is independently selected from C₁₋₃ alkyl and C₁₋₃ haloalkyl;

Ring moiety A is a pyrazole ring, which is optionally substituted by 1,2, or 3 independently selected R^(A) groups;

Ring moiety B is a pyrazole ring, which is optionally substituted by 1,2, or 3 independently selected R^(B) groups;

each R^(A) is independently selected from halo, CN, C₁₋₆ alkyl, and C₁₋₆haloalkyl;

each R^(B) is independently selected from halo, CN, C₁₋₆ alkyl, and C₁₋₆haloalkyl;

n is 1;

m is 0;

s is 0;

R¹ and R² taken together form a linking group L¹; and

L¹ is —CH₂—CH═CH—CH₂—.

In some embodiments:

U is CR^(U);

V is CR^(V);

W is CR^(W);

Q is CR^(Q);

R^(U) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, or C(═O)NR^(c)R^(d);

R^(V) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, or C(═O)NR^(c)R^(d);

R^(W) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, or C(═O)NR^(c)R^(d);

R^(Q) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a), orC(═O)NR^(c)R^(d);

R^(a) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R⁸ groups;

each R⁸ is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, amino, C₁₋₃ alkylamino, and di(C₁₋₃ alkyl)amino;

each R^(c) and R^(d) is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl;

X is CR^(X);

Y is CR^(Y) or N;

Z is CR^(Z) or N;

R^(X) is selected from H, D, halo, CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R³ is H;

R⁵, R⁶, and R⁷ are each independently selected from H, halo, CN, OH,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, carbamyl, C₁₋₆ alkylcarbamyl, anddi(C₁₋₆ alkyl)carbamyl;

R⁴ is H, C₁₋₆ alkyl, or OR^(a4);

R^(a4) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R^(4a) groups;

each R^(4a) is independently selected from CN, OR^(a9), C(═O)R^(b9),C(═O)NR^(c9)R^(d9), C(═O)OR^(a9), OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9),NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9), and NR^(c9)S(═O)₂R^(b9),NR^(c9)S(═O)₂NR^(c9)R^(d9);

each R^(a9), R^(c9), and R^(d9) independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, wherein said C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,and 5-6 membered heteroaryl are each optionally substituted by 1 or 2independently selected R¹¹ groups;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl, each of which is optionally substituted by 1, 2, or 3independently selected R¹¹ groups;

each R¹¹ is independently selected from C₁₋₃ alkyl and C₁₋₃ haloalkyl;

Ring moiety A is a pyrazole ring, which is optionally substituted by 1,2, or 3 independently selected R^(A) groups;

Ring moiety B is a pyrazole ring, which is optionally substituted by 1,2, or 3 independently selected R^(B) groups;

each R^(A) is independently selected from halo, CN, C₁₋₆ alkyl, and C₁₋₆haloalkyl;

each R^(B) is independently selected from halo, CN, C₁₋₆ alkyl, and C₁₋₆haloalkyl;

n is 1;

m is 0;

s is 0;

R¹ and R² taken together form a linking group L¹; and

L¹ is —CH₂—CH═CH—CH₂—.

The following formulas can be combined with any of the aforementionedembodiments.

In some embodiments, the compound is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (V):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (VI):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (VII):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IIa):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IIIa):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IVa):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (Va):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (VIa):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (VIIa):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (VIII):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (IX):

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of Formula (X):

R^(V) is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, carbamyl, or C₁₋₄alkylcarbamyl;

R^(U) and R^(W) are each independently selected from H, halo, CN, C₁₋₄alkyl, and C₁₋₄ haloalkyl;

R^(Q) is selected from H, C₁₋₆ alkyl, OR^(a), and OR^(f), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selected R⁸groups;

R^(a) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R⁸ groups;

R^(f) is C₁₋₆ alkyl which is substituted with 1 substituent selectedfrom R⁹⁰ and —NHR⁸⁰;

each R⁸ is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a8), C(═O)OR^(a8), OC(═O)R^(b8), OC(═O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8), NHC(═O)NHR^(d8), NR^(c8)S(═O)₂R^(b8),and NR^(c8)C(═O)OR^(b8);

each R^(a8), R^(c8), and R^(d8) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, wherein said C₁₋₆ alkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl are each optionally substituted with 1 or 2 independentlyselected R¹⁰ groups;

each R^(b8) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 independently selected R¹⁰ groups;

each R¹⁰ is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a10), NR^(c10)R^(d10), and C(═O)OR^(a10), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selectedR^(G) groups;

each R^(a10) is independently selected from H and C₁₋₆ alkyl, whereinsaid C₁₋₆ alkyl is optionally substituted with 1 or 2 independentlyselected R^(G) groups;

R⁸⁰ is a linear peptide chain having 2-4 amino acids;

R⁹⁰ is a linear chain of formula —(O—C₂₋₄ alkylene)_(z)-R^(G), wherein zis 1, 2, 3, or 4;

Y is N or CR^(Y);

Z is N or CR^(Z);

wherein at least one of Y or Z is N;

R^(X), R^(Y), and R^(Z) are each independently selected from H, halo,CN, C₁₋₃ alkyl, and C₁₋₃ haloalkyl;

Ring moiety A is a pyrazole ring, which is optionally substituted by 1,2, or 3 independently selected R^(A) groups;

Ring moiety B is a pyrazole ring, which is optionally substituted by 1,2, or 3 independently selected R^(B) groups;

L¹ is selected from -R-R- and -R-R-R-;

each R is independently C₁₋₃ alkylene or C₂₋₃ alkenylene;

each R^(A) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(B) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R⁴ is selected from H, C₁₋₆ alkyl, OR^(a4), and OR^(f4), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selectedR^(4a) groups;

R⁶ is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, carbamyl, or C₁₋₄alkylcarbamyl;

R⁵ and R⁷ are each independently selected from H, halo, CN, C₁₋₄ alkyl,and C₁₋₄ haloalkyl;

R^(a4) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R⁸ groups;

R^(f4) is C₁₋₆ alkyl which is substituted with 1 substituent selectedfrom R⁹⁰ and —NHR⁸⁰;

each R^(4a) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a9), C(═O)OR^(a9), OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9),NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9), NHC(═O)NHR^(d9), NR^(c9)S(═O)₂R^(b9),and NR^(c9)C(═O)OR^(b9);

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl, wherein said C₁₋₆ alkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl are each optionally substituted with 1 or 2 independentlyselected R¹¹ groups;

each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 independently selected R¹¹ groups;

each R¹¹ is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a1), NR^(c11)R^(d11), and C(═O)OR^(a11), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selectedR^(G) groups;

each R^(a11) is independently selected from H and C₁₋₆ alkyl, whereinsaid C₁₋₆ alkyl is optionally substituted with 1 or 2 independentlyselected R^(G) groups;

each R^(c11) and R^(d11) independently selected from H and C₁₋₆ alkyl,wherein said C₁₋₆ alkyl is optionally substituted with 1 or 2independently selected R^(G) groups;

each R^(G) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.

In some embodiments of the compounds of Formula (X):

R^(V) is H or carbamyl;

R^(U) and R^(W) are each independently selected from H, halo, CN, andC₁₋₃ alkyl;

R^(Q) is selected from H, C₁₋₆ alkyl, OR^(a), and OR^(f);

R^(a) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R⁸ groups;

each R⁸ is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a8), C(═O)OR^(a8), OC(═O)R^(b8), OC(═O)NR^(c8)R^(d8),NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8), NHC(═O)NHR^(d8), NR^(c8)S(═O)₂R^(b8),and NR^(c8)C(═O)OR^(b8);

each R^(a8), R^(c8), and R^(d8) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1 or 2 independently selected R¹⁰ groups;

each R^(b8) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,and 5-membered heteroaryl, wherein said C₁₋₆ alkyl and 5-memberedheteroaryl are each optionally substituted with 1 or 2 independentlyselected R¹⁰ groups;

each R¹⁰ is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a1), NR^(c10)R^(d10), and C(═O)OR^(a10), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selectedR^(G) groups;

each R^(a10) is independently selected from H and C₁₋₆ alkyl, whereinsaid C₁₋₆ alkyl is optionally substituted with 1 or 2 independentlyselected R^(G) groups;

Y is N or CR^(Y);

Z is N or CR^(Z);

wherein at least one of Y or Z is N;

R^(X), R^(Y), and R^(Z) are each independently selected from H, halo,CN, C₁₋₃ alkyl, and C₁₋₃ haloalkyl;

Ring moiety A is a pyrazole ring, which is optionally substituted by 1or 2 independently selected R^(A) groups;

Ring moiety B is a pyrazole ring, which is optionally substituted by 1or 2 independently selected R^(B) groups;

L¹ is C₃₋₆ alkenylene;

each R^(A) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

each R^(B) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;

R⁴ is selected from H, C₁₋₆ alkyl, OR^(a4), and OR^(f4), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selectedR^(4a) groups;

R⁶ is H or carbamyl;

R⁵ and R⁷ are each independently selected from H, halo, CN, and C₁₋₃alkyl;

R^(a4) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R^(4a) groups;

R^(f4) is C₁₋₆ alkyl which is substituted with 1 substituent selectedfrom R⁹⁰ and —NHR⁸⁰;

each R^(4a) is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a9), OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9),NR^(c9)C(═O)R^(b9), NHC(═O)NHR^(d9), NR^(c9)S(═O)₂R^(b9), andNR^(c9)C(═O)OR^(b9);

R⁸⁰ is a linear peptide chain having 2-4 amino acids;

R⁹⁰ is a linear chain of formula —(O—C₂₋₄ alkylene)_(z)-R^(G), wherein zis 1, 2, 3, or 4;

each R^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionallysubstituted with 1 or 2 independently selected R¹¹ groups;

each R^(b9) is independently C₁₋₆ alkyl, which is optionally substitutedwith 1 or 2 independently selected R¹¹ groups;

each R¹¹ is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a11), NR^(c11)R^(d11), and C(═O)OR^(a11), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selectedR^(G) groups;

each R^(a11) is independently selected from H and C₁₋₆ alkyl, whereinsaid C₁₋₆ alkyl is optionally substituted with 1 or 2 independentlyselected R^(G) groups;

each R^(c11) and R^(d11) independently selected from H and C₁₋₆ alkyl,wherein said C₁₋₆ alkyl is optionally substituted with 1 or 2independently selected R^(G) groups; and

each R^(G) is independently selected from H, OH, CN, halo, C₁₋₃ alkyl,C₁₋₃ alkoxy, C₁₋₃ amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, andcarboxy.

In further embodiments of the compounds of Formula (X), Ring moiety A isa pyrazole ring, which is optionally substituted by 1 or 2 independentlyselected R^(A) groups; Ring moiety B is a pyrazole ring, which isoptionally substituted by 1 or 2 independently selected R^(B) groups;each R^(A) and R^(B) is independently selected from C₁₋₄ alkyl; and L¹is —CH₂—CH═CH—CH₂—.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency, that the designated atom's normalvalency is not exceeded, and that the substitution results in a stablecompound.

As used herein, the phrase “each ‘variable’ is independently selectedfrom” means substantially the same as wherein “at each occurrence‘variable’ is selected from.”

When any variable (e.g., R⁸) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 1, 2, 3, or 4 R⁸,then said group may optionally be substituted with up to four R⁸ groupsand R⁸ at each occurrence is selected independently from the definitionof R⁸. Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds; forexample the combination of a first M group and second M group in thecombination of two R groups are permissible only if such combinations ofM-M result in stable compounds.

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl,tert-butyl, isobutyl, sec-butyl; higher homologs such as2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl,and the like. In some embodiments, the alkyl group contains from 1 to 6carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, theterm “C_(n-m) alkoxy”, employed alone or in combination with otherterms, refers to a group of formula-O-alkyl, wherein the alkyl group hasn to m carbons. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g.,n-butoxy and tert-butoxy), and the like. In some embodiments, the alkylgroup has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m) aryl” refers to an aryl group having from n to m ring carbonatoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, thearyl group has from 5 to 10 carbon atoms. In some embodiments, the arylgroup is phenyl or naphthyl. In some embodiments, the aryl is phenyl.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments,halo is F, Cl, or Br.

In some embodiments, halo is F or Cl. In some embodiments, halo is F. Insome embodiments, halo is Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. Example haloalkoxy groupsinclude OCF₃ and OCHF₂. In some embodiments, the haloalkoxy group isfluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “cyano-C₁₋₆ alkyl” refers to a group of formula—(C₁₋₆ alkylene)-CN.

As used herein, the term “HO—C₁₋₆ alkyl” refers to a group of formula—(C₁₋₆ alkylene)-OH.

As used herein, the term “C₁₋₆ alkoxy-C₁₋₆ alkyl” refers to a group offormula —(C₁₋₆ alkylene)-O(C₁₋₆ alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyloxy” is a group offormula —OC(O)-alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, “aminocarbonyloxy” is a group of formula —OC(O)—NH₂.

As used herein, “C_(n-m) alkylaminocarbonyloxy” is a group of formula—OC(O)—NH-alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, “di(C_(n-m) alkyl)aminocarbonyloxy” is a group offormula —OC(O)—N(alkyl)₂, wherein each alkyl group has, independently, nto m carbon atoms.

As used herein C_(n-m) alkoxycarbonylamino refers to a group of formula—NHC(O)—O-alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups,spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group).Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of cyclopentane, cyclohexane,and the like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13 or 14 ring-forming carbons (i.e., C₃₋₁₄). In someembodiments, the cycloalkyl is a C₃₋₁₄ monocyclic or bicycliccycloalkyl. In some embodiments, the cycloalkyl is a C₃₋₇ monocycliccycloalkyl. In some embodiments, the cycloalkyl is a C₄₋₇ monocycliccycloalkyl. In some embodiments, the cycloalkyl is a C₄₋₁₀ spirocycle orbridged cycloalkyl (e.g., a bridged bicycloalkyl group). Examplecycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane,bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g.,having 2, 3, or 4 fused rings) aromatic heterocycle having at least oneheteroatom ring member selected from N, O, S and B. In some embodiments,the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring membersindependently selected from N, O, S and B. In some embodiments, anyring-forming N in a heteroaryl moiety can be an N-oxide. In someembodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclicheteroaryl having 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, O, S and B. In some embodiments, the heteroaryl is a5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4heteroatom ring members independently selected from N, O, S and B. Insome embodiments, the heteroaryl is a 5-10 membered monocyclic orbicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring membersindependently selected from N, O, and S. In some embodiments, theheteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ringmembers independently selected from N, O, S and B. In some embodiments,the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatomring members independently selected from N, O, and S. In someembodiments, the heteroaryl group contains 5-10 or 5-6 ring-formingatoms. In some embodiments, the heteroaryl group has 1 to 4 ring-formingheteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-formingheteroatoms or 1 ring-forming heteroatom. When the heteroaryl groupcontains more than one heteroatom ring member, the heteroatoms may bethe same or different. Example heteroaryl groups include, but are notlimited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole,pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole,furan, thiophene, triazole, tetrazole, thiadiazole, quinoline,isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole,imidazo[1, 2-b]thiazole, purine, triazine, thieno[3,2-b]pyridine,imidazo[1,2-a]pyridine, 1,5-naphthyridine, 1H-pyrazolo[4,3-b]pyridine,and the like.

A five-membered heteroaryl is a heteroaryl group having fivering-forming atoms wherein one or more (e.g., 1, 2, or 3) of thering-forming atoms are independently selected from N, O, S or B.Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl,imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl and 1,2-dihydro-1,2-azaborine.

A six-membered heteroaryl ring is a heteroaryl with a ring having sixring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms areindependently selected from N, O, S and B. Exemplary six-membered ringheteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl andpyridazinyl.

As used herein, “heterocycloalkyl” refers to monocyclic or polycyclicheterocycles having at least one non-aromatic ring (saturated orpartially unsaturated ring), wherein one or more of the ring-formingcarbon atoms of the heterocycloalkyl is replaced by a heteroatomselected from N, O, S and B, wherein the ring-forming carbon atoms andheteroatoms of a heterocycloalkyl group can be optionally substituted byone or more oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)₂, etc.).Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having2, 3 or 4 fused rings) systems. Included in heterocycloalkyl aremonocyclic and polycyclic 3-14 or 4-14 membered heterocycloalkyl groups.Heterocycloalkyl groups can also include spirocycles and bridged rings(e.g., a 5-14 membered bridged biheterocycloalkyl ring having one ormore of the ring-forming carbon atoms replaced by a heteroatom selectedfrom N, O, S and B). The heterocycloalkyl group can be attached througha ring-forming carbon atom or a ring-forming heteroatom. In someembodiments, the heterocycloalkyl group contains 0 to 3 double bonds. Insome embodiments, the heterocycloalkyl group contains 0 to 2 doublebonds. Also included in the definition of heterocycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the non-aromatic heterocyclic ring, for example, benzoor thienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. In some embodiments, the heterocycloalkyl group contains3 to 14 ring-forming atoms, 4 to 14 ring-forming atoms, 3 to 7ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments,the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1to 2 heteroatoms or 1 heteroatom. In some embodiments, theheterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1or 2 heteroatoms independently selected from N, O, S and B and havingone or more oxidized ring members.

In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic5-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatomsindependently selected from N, O, S and B and having one or moreoxidized ring members. In some embodiments, the heterocycloalkyl is amonocyclic or bicyclic 5-10 membered heterocycloalkyl having 1, 2, 3, or4 heteroatoms independently selected from N, O, and S and having one ormore oxidized ring members. In some embodiments, the heterocycloalkyl isa monocyclic 5-6 membered heterocycloalkyl having 1, 2, 3, or 4heteroatoms independently selected from N, O, and S and having one ormore oxidized ring members. Example heterocycloalkyl groups includepyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran,oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl,isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,thiazolidinyl, imidazolidinyl, azepanyl, benzazapene,azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl,oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl,diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl,diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl,diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl,azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl,oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl,oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl,azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl,azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxa-diazaspiro[4.4]nonanyl and the like. In some embodiments, exampleheterocycloalkyl group are pyrrolidonyl, pyrrolidin-2-one,1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl,morpholinyl, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, and 1,2,3,4-tetrahydroisoquinoline.

As used herein, “C_(o-p) cycloalkyl-C_(n-m) alkyl-” refers to a group offormula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbonatoms and the alkylene linking group has n to m carbon atoms.

As used herein “C_(o-p) aryl-C_(n-m) alkyl-” refers to a group offormula aryl-alkylene-, wherein the aryl has o to p carbon atoms and thealkylene linking group has n to m carbon atoms.

As used herein, “heteroaryl-C_(n-m) alkyl-” refers to a group of formulaheteroaryl-alkylene-, wherein alkylene linking group has n to m carbonatoms.

As used herein “heterocycloalkyl-C_(n-m) alkyl-” refers to a group offormula heterocycloalkyl-alkylene-, wherein alkylene linking group has nto m carbon atoms.

As used herein, an “alkyl linking group” is a bivalent straight chain orbranched alkyl linking group (“alkylene group”). For example, “C_(o-p)cycloalkyl-C_(n-m) alkyl-”, “C_(o-p) aryl-C_(n-m) alkyl-”,“phenyl-C_(n-m) alkyl-”, “heteroaryl-C_(n-m) alkyl-”, and“heterocycloalkyl-C_(n-m) alkyl-” contain alkyl linking groups. Examplesof “alkyl linking groups” or “alkylene groups” include methylene,ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl, propan-1,2-diyl,propan-1,1-diyl and the like.

As used herein, the term “one of R^(A) and one of R^(B) taken togetherform a linking group L²” means i) ring moiety A has been substitutedwith at least one R^(A) group ortho to the bond connecting ring A to thetricyclic heterocycle containing X, Y, and Z, ii) ring moiety B has beensubstituted with at least one R^(B) group ortho to the bond connectingring B to the —NR³—C(═O)-amide, and iii) taken together R^(A) and R^(B)form the linking group L² the definition of which is indepedendent ofthe defijiitons of substitutents R^(A) and R^(B) before combination.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

As used herein, the term “oxo” refers to an oxygen atom (i.e., ═O) as adivalent substituent, forming a carbonyl group when attached to a carbon(e.g., C═O or C(O)), or attached to a nitrogen or sulfur heteroatomforming a nitroso, sulfinyl or sulfonyl group.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such as0-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. The present disclosure also includespharmaceutically acceptable salts of the compounds described herein. Asused herein, “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified byconverting an existing acid or base moiety to its salt form. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts of the present disclosureinclude the conventional non-toxic salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present disclosure can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

Synthesis

As will be appreciated, the compounds provided herein, including saltsand stereoisomers thereof, can be prepared using known organic synthesistechniques and can be synthesized according to any of numerous possiblesynthetic routes.

Compounds of formula 1-10 can be synthesized using a process shown inScheme 1. Nucleophilic aromatic substitution of an appropriatelyfunctionalized nitro-halo-phenyl compound 1-1 with an amine containing alinker group L¹ 1-2 can afford compound 1-3. Reduction of the aromaticnitro group followed by ring closing reaction with cyanogen bromide canprovide the aminobenzimidazole 1-5. Amide coupling of compound 1-5 withcarboxylic acid 1-6 can generate the aminobenzimidazole 1-7. Removal ofthe Boc protecting group in 1-7 can afford the amine 1-8 which can beconverted to the alcohol 1-9 under Sandmeyer conditions. The compound1-10 could be achieved by reacting the alcohol 1-9 with phosphorus (III)bromide.

Compounds of formula 2-8 can be synthesized using a process shown inScheme 2. Palladium-catalyzed cross-coupling reactions of theappropriate aryl halides and boronic acids/esters can produce the biarylcompounds of formula 2-5. Under deoxygenation conditions, the in-situgenerated nitrene from compound 2-5 can insert into the adjacentaromatic C-H bond and afford the tricyclic compound 2-6. Suzuki couplingof the aryl-Cl 2-6 with aromatic boronic ester 2-7 can furnish thecompounds of formula 2-8.

As shown in Scheme 3, reactions of compounds 3-1 and 3-2 under basicconditions can afford the compound of formula 3-3.

Compounds of formula 4-7 can be synthesized using a process shown inScheme 4. Reagents 4-1 and 4-2 can be coupled with the suitable linkerto form compound 4-3. Two consecutive palladium-catalyzed cross-couplingreactions of the aryl halides and boronic acids/esters can providecompounds of formula 4-5. Under deoxygenation conditions, the in-situgenerated nitrene can insert into the adjacent aromatic C-H bond andafford the tricyclic compound 4-6. Finally, N-functionalization on thetricycle can generate the target molecule 4-7.

Compounds of formula 5-8 can be synthesized using a process shown inScheme 5. Reagents 5-1 and 5-2 can be coupled with the suitable linkerto form compound 5-3. Two consecutive palladium-catalyzed cross-couplingreactions of the aryl halides and boronic acids/esters can providecompounds of formula 5-5. Under deoxygenation conditions, the in-situgenerated nitrene can insert into the adjacent aromatic C-H bond andafford the tricyclic compound 5-6. Using similar conditions as shown inScheme 1, the compound 5-7 could be achieved from the amine 5-6.Finally, the target molecule 5-8 can be accessed via an intramolecularsubstitution reaction.

Compounds of formula 6-5 can be synthesized using a process shown inScheme 6. Reagents 6-1 and 6-2 can be coupled with the suitable linkerto form compound 6-3. Amide coupling of molecule 6-3 with2-amino-benzimidazole 6-4 can generate the target molecule 6-5.

Compounds of formula 7-5 can be synthesized using a process shown inScheme 7. Reagents 7-1 and 7-2 can be coupled with the suitable linkerto form compound 7-3. Using similar conditions as shown in Scheme 1, thecompound 7-4 could be achieved from the amine 7-3. Finally, targetcompounds 7-5 can be accessed via an intramolecular substitution stepunder basic conditions.

Compounds of formula 8-6 can be synthesized using a process shown inScheme 8. Reagents 8-1 and 8-2 can be coupled with the suitable linkerto form compound 8-3. Next, reagent 8-3 could be further coupled withcompound 8-4 by linker L³ to access intermediate 8-5. Finally, targetcompounds 8-6 can be accessed via an intramolecular amide coupling step.

Methods of Use

Compounds of the present disclosure can activate STING-mediated IRF3 andNFκB signaling pathways to produce type I interferons andproinflammatory chemokines and cytokines and, thus, are useful intreating infectious diseases and cancer. In certain embodiments, thecompounds of the present disclosure, or pharmaceutically acceptablesalts or stereoisomers thereof, are useful for therapeuticadministration to enhance, stimulate and/or increase immunity in cancer,chronic infection or sepsis, including enhancement of response tovaccination. In some embodiments, the present disclosure provides amethod for inducing STING-mediated IRF3 and NFκB pathway activation. Themethod includes administering to an individual or a patient a compoundof Formula (I) or of any of the formulas as described herein, or of acompound as recited in any of the claims and described herein, or apharmaceutically acceptable salt or a stereoisomer thereof. Thecompounds of the present disclosure can be used alone, in combinationwith other agents or therapies or as an adjuvant or neoadjuvant for thetreatment of diseases or disorders, including cancer or infectiondiseases. For the uses described herein, any of the compounds of thedisclosure, including any of the embodiments thereof, may be used.

The compounds of the present disclosure activate STING, resulting inIRF3 and NFκB upregulation and production of IFNs and other cytokines.The production of those interferons and proinflammatory cytokines canenhance the immune response to cancerous cells and infectious diseasesin mammals, including humans. In some embodiments, the presentdisclosure provides treatment of an individual or a patient in vivousing a compound of Formula (I) or a salt or stereoisomer thereof suchthat growth of cancerous tumors is inhibited. A compound of Formula (I)or of any of the formulas as described herein, or a compound as recitedin any of the claims and described herein, or a salt or stereoisomerthereof, can be used to inhibit the growth of cancerous tumors.Alternatively, a compound of Formula (I) or of any of the formulas asdescribed herein, or a compound as recited in any of the claims anddescribed herein, or a salt or stereoisomer thereof, can be used inconjunction with other agents or standard cancer treatments, asdescribed below. In one embodiment, the present disclosure provides amethod for inhibiting growth of tumor cells in vitro. The methodincludes contacting the tumor cells in vitro with a compound of Formula(I) or of any of the formulas as described herein, or of a compound asrecited in any of the claims and described herein, or of a salt orstereoisomer thereof. In another embodiment, the present disclosureprovides a method for inhibiting growth of tumor cells in an individualor a patient. The method includes administering to the individual orpatient in need thereof a therapeutically effective amount of a compoundof Formula (I) or of any of the formulas as described herein, or of acompound as recited in any of the claims and described herein, or a saltor a stereoisomer thereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Examples of cancersinclude those whose growth may be inhibited using compounds of thedisclosure and cancers typically responsive to immunotherapy.

In some embodiments, the present disclosure provides a method ofenhancing, stimulating and/or increasing the immune response in apatient. The method includes administering to the patient in needthereof a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound or composition asrecited in any of the claims and described herein, or a salt thereof.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, colon cancer, lungcancer (e.g. non-small cell lung cancer and small cell lung cancer),squamous cell head and neck cancer, urothelial cancer (e.g. bladder) andcancers with high microsatellite instability (MSI^(high)). Additionally,the disclosure includes refractory or recurrent malignancies whosegrowth may be inhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to,cholangiocarcinoma, bile duct cancer, triple negative breast cancer,rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellularcarcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma,neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma,epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinalcancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinalcancer, islet cell cancer, oral cancer, mouth cancer, throat cancer,laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavitycancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer,renal cell carcinoma, salivary gland cancer, sinus cancer, spinalcancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteralcancer.

In some embodiments, the compounds of the present disclosure can be usedto treat sickle cell disease and sickle cell anemia.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), and essential thrombocytosis (ET)),myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma(T-ALL) and multiple myeloma (MM).

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, and keloids. In some embodiments, diseases andindications that are treatable using the compounds of the presentdisclosure include, but are not limited to, sickle cell disease (e.g.,sickle cell anemia), triple-negative breast cancer (TNBC),myelodysplastic syndromes, testicular cancer, bile duct cancer,esophageal cancer, and urothelial carcinoma.

Induction of type I interferons and other proinflammatorycytokines/chemokines with compounds of the present disclosure can alsobe used for treating infections such as viral, bacteria, fungus andparasite infections. The present disclosure provides a method fortreating infections such as viral infections. The method includesadministering to a patient in need thereof, a therapeutically effectiveamount of a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,a salt thereof. Examples of viruses causing infections treatable bymethods of the present disclosure include, but are not limit to, humanimmunodeficiency virus, human papillomavirus, influenza, hepatitis A, B,C or D viruses, adenovirus, poxvirus, herpes simplex viruses, humancytomegalovirus, severe acute respiratory syndrome virus, ebola virus,and measles virus. In some embodiments, viruses causing infectionstreatable by methods of the present disclosure include, but are notlimit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6,HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus,flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus,respiratory syncytial virus, mumpsvirus, rotavirus, measles virus,rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus,papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus,tuberculosis and arboviral encephalitis virus.

The present disclosure provides a method for treating bacterialinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic bacteria causing infections treatable by methodsof the disclosure include chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria,salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague,leptospirosis, and Lyme's disease bacteria.

The present disclosure provides a method for treating fungus infections.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Non-limiting examples ofpathogenic fungi causing infections treatable by methods of thedisclosure include Candida (albicans, krusei, glabrata, tropicalis,etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.),Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii,Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioidesimmitis and Histoplasma capsulatum.

The present disclosure provides a method for treating parasiteinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic parasites causing infections treatable by methodsof the disclosure include Entamoeba histolytica, Balantidium coli,Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp.,Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosomabrucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, andNippostrongylus brasiliensis.

The present disclosure provides a method for treating neurodegenerativediseases or disorders. The method includes administering to a patient inneed thereof, a therapeutically effective amount of a compound ofFormula (I) or any of the formulas as described herein, a compound asrecited in any of the claims and described herein, or a salt thereof.Non-limiting examples of neurodegenerative diseases or disorders includeAlzheimer's disease, Parkinson's disease, Huntington's disease, priondisease, Motor neurone diseases, Spinocerebellar ataxia and Spinalmuscular atrophy.

It is believed that compounds of Formula (I), or any of the embodimentsthereof, may possess satisfactory pharmacological profile and promisingbiopharmaceutical properties, such as toxicological profile, metabolismand pharmacokinetic properties, solubility, and permeability. It will beunderstood that determination of appropriate biopharmaceuticalproperties is within the knowledge of a person skilled in the art, e.g.,determination of cytotoxicity in cells or inhibition of certain targetsor channels to determine potential toxicity.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease. Compounds of thepresent disclosure can activate STING-mediated IRF3 and NFκB signalingpathways to produce type I interferons and proinflammatory chemokinesand cytokines and, thus, are useful in treating infectious diseases andcancer. In certain embodiments, the compounds of the present disclosure,or pharmaceutically acceptable salts or stereoisomers thereof, areuseful for therapeutic administration to enhance, stimulate and/orincrease immunity in cancer, chronic infection or sepsis, includingenhancement of response to vaccination. In some embodiments, the presentdisclosure provides a method for inducing STING-mediated IRF3 and NFκBpathway activation. The method includes administering to an individualor a patient a compound of Formula (I) or of any of the formulas asdescribed herein, or of a compound as recited in any of the claims anddescribed herein, or a pharmaceutically acceptable salt or astereoisomer thereof. The compounds of the present disclosure can beused alone, in combination with other agents or therapies or as anadjuvant or neoadjuvant for the treatment of diseases or disorders,including cancer or infection diseases. For the uses described herein,any of the compounds of the disclosure, including any of the embodimentsthereof, may be used.

The compounds of the present disclosure activate STING, resulting inIRF3 and NFκB upregulation and production of IFNs and other cytokines.The production of those interferons and proinflammatory cytokines canenhance the immune response to cancerous cells and infectious diseasesin mammals, including humans. In some embodiments, the presentdisclosure provides treatment of an individual or a patient in vivousing a compound of Formula (I) or a salt or stereoisomer thereof suchthat growth of cancerous tumors is inhibited. A compound of Formula (I)or of any of the formulas as described herein, or a compound as recitedin any of the claims and described herein, or a salt or stereoisomerthereof, can be used to inhibit the growth of cancerous tumors.Alternatively, a compound of Formula (I) or of any of the formulas asdescribed herein, or a compound as recited in any of the claims anddescribed herein, or a salt or stereoisomer thereof, can be used inconjunction with other agents or standard cancer treatments, asdescribed below. In one embodiment, the present disclosure provides amethod for inhibiting growth of tumor cells in vitro. The methodincludes contacting the tumor cells in vitro with a compound of Formula(I) or of any of the formulas as described herein, or of a compound asrecited in any of the claims and described herein, or of a salt orstereoisomer thereof. In another embodiment, the present disclosureprovides a method for inhibiting growth of tumor cells in an individualor a patient. The method includes administering to the individual orpatient in need thereof a therapeutically effective amount of a compoundof Formula (I) or of any of the formulas as described herein, or of acompound as recited in any of the claims and described herein, or a saltor a stereoisomer thereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Examples of cancersinclude those whose growth may be inhibited using compounds of thedisclosure and cancers typically responsive to immunotherapy.

In some embodiments, the present disclosure provides a method ofenhancing, stimulating and/or increasing the immune response in apatient. The method includes administering to the patient in needthereof a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound or composition asrecited in any of the claims and described herein, or a salt thereof.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, colon cancer, lungcancer (e.g. non-small cell lung cancer and small cell lung cancer),squamous cell head and neck cancer, urothelial cancer (e.g. bladder) andcancers with high microsatellite instability (MSI^(high)). Additionally,the disclosure includes refractory or recurrent malignancies whosegrowth may be inhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to,cholangiocarcinoma, bile duct cancer, triple negative breast cancer,rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellularcarcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma,neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma,epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinalcancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinalcancer, islet cell cancer, oral cancer, mouth cancer, throat cancer,laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavitycancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer,renal cell carcinoma, salivary gland cancer, sinus cancer, spinalcancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteralcancer.

In some embodiments, the compounds of the present disclosure can be usedto treat sickle cell disease and sickle cell anemia.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), and essential thrombocytosis (ET)),myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma(T-ALL) and multiple myeloma (MM).

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, and keloids. In some embodiments, diseases andindications that are treatable using the compounds of the presentdisclosure include, but are not limited to, sickle cell disease (e.g.,sickle cell anemia), triple-negative breast cancer (TNBC),myelodysplastic syndromes, testicular cancer, bile duct cancer,esophageal cancer, and urothelial carcinoma.

Induction of type I interferons and other proinflammatorycytokines/chemokines with compounds of the present disclosure can alsobe used for treating infections such as viral, bacteria, fungus andparasite infections. The present disclosure provides a method fortreating infections such as viral infections. The method includesadministering to a patient in need thereof, a therapeutically effectiveamount of a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,a salt thereof. Examples of viruses causing infections treatable bymethods of the present disclosure include, but are not limit to, humanimmunodeficiency virus, human papillomavirus, influenza, hepatitis A, B,C or D viruses, adenovirus, poxvirus, herpes simplex viruses, humancytomegalovirus, severe acute respiratory syndrome virus, ebola virus,and measles virus. In some embodiments, viruses causing infectionstreatable by methods of the present disclosure include, but are notlimit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6,HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus,flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus,respiratory syncytial virus, mumpsvirus, rotavirus, measles virus,rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus,papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus,tuberculosis and arboviral encephalitis virus.

The present disclosure provides a method for treating bacterialinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic bacteria causing infections treatable by methodsof the disclosure include chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria,salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague,leptospirosis, and Lyme's disease bacteria.

The present disclosure provides a method for treating fungus infections.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Non-limiting examples ofpathogenic fungi causing infections treatable by methods of thedisclosure include Candida (albicans, krusei, glabrata, tropicalis,etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.),Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii,Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioidesimmitis and Histoplasma capsulatum.

The present disclosure provides a method for treating parasiteinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic parasites causing infections treatable by methodsof the disclosure include Entamoeba histolytica, Balantidium coli,Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp.,Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosomabrucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, andNippostrongylus brasiliensis.

The present disclosure provides a method for treating neurodegenerativediseases or disorders. The method includes administering to a patient inneed thereof, a therapeutically effective amount of a compound ofFormula (I) or any of the formulas as described herein, a compound asrecited in any of the claims and described herein, or a salt thereof.Non-limiting examples of neurodegenerative diseases or disorders includeAlzheimer's disease, Parkinson's disease, Huntington's disease, priondisease, Motor neurone diseases, Spinocerebellar ataxia and Spinalmuscular atrophy.

It is believed that compounds of Formula (I), or any of the embodimentsthereof, may possess satisfactory pharmacological profile and promisingbiopharmaceutical properties, such as toxicological profile, metabolismand pharmacokinetic properties, solubility, and permeability. It will beunderstood that determination of appropriate biopharmaceuticalproperties is within the knowledge of a person skilled in the art, e.g.,determination of cytotoxicity in cells or inhibition of certain targetsor channels to determine potential toxicity.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

I. Immune-Checkpoint Therapies

Compounds of the present disclosure can be used in combination with oneor more inhibitors or agonists of an immune checkpoint molecule for thetreatment of diseases, such as cancer or infections. Exemplary immunecheckpoint molecules such as CBL-B, CD20, CD27, CD28, CD40, CD122, CD96,CD73, CD47, CD160, KIR, LAIR1, 2B4, TGF beta, GITR, CSF1R, JAK, PI3Kdelta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB),ICOS, A2AR, IDO, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TIGIT, CD112R,VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the compounds of thepresent disclosure can be used in combination with an inhibitor of animmune checkpoint molecule. In some embodiments, the compounds of thepresent disclosure can be used in combination with an agonist of animmune checkpoint molecule. In some embodiments, the inhibitor oragonist of the immune checkpoint molecule is an antibody, orantigen-binding fragment thereof. In some embodiments, the inhibitor oragonist of the immune checkpoint molecule is a small molecule, or apharmaceutically acceptable salt thereof. In some embodiments, theimmune checkpoint molecule is a stimulatory checkpoint molecule selectedfrom CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments,the immune checkpoint molecule is an inhibitory checkpoint moleculeselected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1,TIM3, TIGIT, and VISTA. In some embodiments, the compounds providedherein can be used in combination with one or more inhibitors of animmune checkpoint molecule selected from KIR inhibitors, TIGITinhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFbeta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD 1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. Antibodiesthat bind to human PD-1 include nivolumab, pembrolizumab, cemiplimab,spartalizumab, camrelizumab, cetrelimab, toripalimab, sintilimab, AB122,AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, andTSR-042. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210,PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, theanti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In someembodiments, the anti-PD 1 antibody is pembrolizumab. In someembodiments, the anti-PD-1 monoclonal antibody is MGA012. In someembodiments, the anti-PD 1 antibody is SHR-1210. Other anti-canceragent(s) include antibody therapeutics such as 4-1BB (e.g. urelumab,utomilumab).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody.Antibodies that bind to human PD-L1 include atezolizumab, avelumab,durvalumab, tislelizumab, BMS-935559, MEDI4736, FAZ053, KN035, CS1001,SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20,and LY3300054. In some embodiments, the anti-PD-L1 monoclonal antibodyis BMS-935559, MED14736, MPDL3280A (also known as RG7446), durvalumab(Imfinzi®), or MSB0010718C.

In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A orMED14736. In some embodiments, the inhibitor of an immune checkpointmolecule is an inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1bispecific antibody. In some embodiments, the anti-PD-1/PD-L1 isMCLA-136.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the inhibitor of CTLA-4 is ipilimumab, tremelimumab,AGEN1884, or CP-675,206. In some embodiments, the inhibitor of an immunecheckpoint molecule is an inhibitor of PD-L1 and CTLA-4, e.g., ananti-PD-L1/CTLA-4 bispecific antibody. Bispecific antibodies that bindto PD-L1 and CTLA-4 include AK104.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the inhibitor of LAG3 is BMS-986016, LAG525, INCAGN2385, or eftilagimodalpha (IMP321).

In some embodiments, the agonist of CD137 is urelumab. In someembodiments, the agonist of CD137 is utomilumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD73. In some embodiments, the inhibitor of CD73 isoleclumab or MED19447.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT isOMP-31M32.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of VISTA. In some embodiments, the inhibitor of VISTA isJNJ-61610588 or CA-170.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 isenoblituzumab, MGD009, or 8H9.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of KIR. In some embodiments, the inhibitor of KIR islirilumab or IPH4102.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of A2aR. In some embodiments, the inhibitor of A2aR isCPI-444.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-betais trabedersen, galusertinib, or M7824.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PI3K-gamma. In some embodiments, the inhibitor ofPI3K-gamma is IPI-549.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD47. In some embodiments, the inhibitor of CD47 isHu5F9-G4 or TTI-621.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD70. In some embodiments, the inhibitor of CD70 iscusatuzumab or BMS-936561.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the inhibitor of TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule that binds to PD-L1, or a pharmaceutically acceptablesalt thereof. In some embodiments, the inhibitor of an immune checkpointmolecule is a small molecule that binds to and internalizes PD-L1, or apharmaceutically acceptable salt thereof. In some embodiments, theinhibitor of an immune checkpoint molecule is a compound selected fromthose in US 2018/0179201, US 2018/0179197, US 2018/0179179, US2018/0179202, US 2018/0177784, US 2018/0177870, U.S. Ser. No. 16/369,654(filed Mar. 29, 2019), and U.S. Ser. No. 62/688,164 (filed May 11,2019), or a pharmaceutically acceptable salt thereof, each of which isincorporated herein by reference in its entirety.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7/8, and CD137 (alsoknown as 4-1BB).

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of GITR. In some embodiments, the agonist of GITR is TRX518,MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, orMEDI6469.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein. Insome embodiments, the agonist of OX40 is INCAGN01949, MEDI0562(tavolimab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178, or 9B12. Insome embodiments, the OX40L fusion protein is MEDI6383.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD40. In some embodiments, the agonist of CD40 is CP-870893,ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or ChiLob 7/4.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of ICOS. In some embodiments, the agonist of ICOS isGSK-3359609, JTX-2011, or MEDI-570.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD28. In some embodiments, the agonist of CD28 istheralizumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

In some embodiments, the agonist of an immune checkpoint molecule is anagonist of TLR7/8. In some embodiments, the agonist of TLR7/8 isMEDI9197.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor. In some embodiments, the bispecificantibody binds to PD-1 and PD-L1. In some embodiments, the bispecificantibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments,the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments,the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104. In someembodiments, the bispecific antibody binds to PD-L1 and CD137. In someembodiments, the bispecific antibody that binds to PD-L1 and CD137 isMCLA-145.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

II. Cancer Therapies

Cancer cell growth and survival can be impacted by dysfunction inmultiple biological pathways. Thus, it may be useful to combineinhibitors of different mechanisms, such as enzyme inhibitors, signaltransduction inhibitors, inhibitors of chromatin dynamics or modulatorsof immune responses, to treat such conditions. Targeting more than onesignaling pathway (or more than one biological molecule involved in agiven signaling pathway) may reduce the likelihood of drug-resistancearising in a cell population, or reduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitor therapies for thetreatment of diseases, such as cancer, infections, and other diseases ordisorder described herein. Examples of diseases and indicationstreatable with combination therapies include those as described herein.Examples of cancers include solid tumors and non-solid tumors, such asliquid tumors, blood cancers. Examples of infections include viralinfections, bacterial infections, fungus infections or parasiteinfections. For example, the compounds of the present disclosure can becombined with one or more inhibitors of the following kinases for thetreatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK, TGF-βR, PKA, PKG, PKC,CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2,HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha,beta, gamma, delta, and multiple or selective), CSF1R, KIT, FLK-II,KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, PARP, Ron,Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3, VEGFR/Flt2,Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk,Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In some embodiments, thecompounds of the present disclosure can be combined with one or more ofthe following inhibitors for the treatment of cancer or infections.Non-limiting examples of inhibitors that can be combined with thecompounds of the present disclosure for treatment of cancer andinfections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4,e.g., pemigatinib (INCY54828), INCB62079), an EGFR inhibitor (also knownas ErB-1 or HER-1; e.g. erlotinib, gefitinib, vandetanib, orsimertinib,cetuximab, necitumumab, or panitumumab), a VEGFR inhibitor or pathwayblocker (e.g. bevacizumab, pazopanib, sunitinib, sorafenib, axitinib,regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab,lenvatinib, ziv-aflibercept), a PARP inhibitor (e.g. olaparib,rucaparib, veliparib or niraparib), a JAK inhibitor (JAK1 and/or JAK2,e.g., ruxolitinib, baricitinib, itacitinib (INCB39110), an IDO inhibitor(e.g., epacadostat, NLG919, or BMS-986205, MK7162), an LSD1 inhibitor(e.g., INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor(e.g., parsaclisib (INCB50465) and INCB50797), a PI3K-gamma inhibitorsuch as PI3K-gamma selective inhibitor, a Pim inhibitor (e.g.,INCB53914), a CSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3,Axl, and Mer), an adenosine receptor antagonist (e.g., A2a/A2b receptorantagonist), an HPK1 inhibitor, a chemokine receptor inhibitor (e.g.CCR2 or CCR5 inhibitor), a SHP 1/2 phosphatase inhibitor, a histonedeacetylase inhibitor (HDAC) such as an HDAC8 inhibitor, an angiogenesisinhibitor, an interleukin receptor inhibitor, bromo and extra terminalfamily members inhibitors (for example, bromodomain inhibitors or BETinhibitors such as INCB54329 and INCB57643), or combinations thereof.

In some embodiments, the compound or salt described herein isadministered with a PI3Kδ inhibitor. In some embodiments, the compoundor salt described herein is administered with a JAK inhibitor. In someembodiments, the compound or salt described herein is administered witha JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In someembodiments, the compound or salt described herein is administered witha JAK1 inhibitor. In some embodiments, the compound or salt describedherein is administered with a JAK1 inhibitor, which is selective overJAK2.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present disclosure and are presented as a non-limitinglist: a cytostatic agent, taxotere, taxol, etoposide, irinotecan,camptostar, epothilones, 5-fluorouracil, methoxtrexate,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™(gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, intron, ara-C,adriamycin, cytoxan, chlormethine, pipobroman, triethylenemelamine,triethylenethiophosphoramine, 6-mercaptopurine, 6-thioguanine,fludarabine phosphate, leucovirin, ELOXATIN™ (oxaliplatin),pentostatine, vindesine, mithramycin, deoxycoformycin, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,prednisone, fluoxymesterone, megestrolacetate, methylprednisolone,methyltestosterone, prednisolone, triamcinolone, chlorotrianisene,hydroxyprogesterone, aminoglutethimide, medroxyprogesteroneacetate,leuprolide, flutamide, goserelin, hydroxyurea, amsacrine, navelbene,anastrazole, letrazole, reloxafine, droloxafine, hexamethylmelamine,avastin, HERCEPTIN™ (trastuzumab), BEXXAR™ (tositumomab), VELCADE™(bortezomib), ZEVALIN™ (ibritumomab tiuxetan), TRISENOX™ (arsenictrioxide), XELODA™ (capecitabine), porfimer, ERBITUX™ (cetuximab),lerozole, ifosfomide, C225 (cetuximab), Campath (alemtuzumab),aphidicolon, rituxan, tezacitabine, Sml1, pentostatin, triapine, didox,trimidox, amidox, 3-AP, and MDL-101,731.

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, bispecific ormulti-specific antibody, antibody drug conjugate, adoptive T celltransfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor, PI3Kδ inhibitor and the like.

The compounds can be administered in combination with one or moreanti-cancer drugs, such as a chemotherapeutic agent. Examples ofchemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide,asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib,bleomycin, bortezomib, busulfan intravenous, busulfan oral, calusterone,capecitabine, carboplatin, carmustine, cetuximab, chlorambucil,cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine,dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin,decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel,doxorubicin, dromostanolone propionate, eculizumab, epirubicin,erlotinib, estramustine, etoposide phosphate, etoposide, exemestane,fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinibditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate,levamisole, lomustine, meclorethamine, megestrol acetate, melphalan,mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane,mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab,oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase,pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin,procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,vorinostat and zoledronate.

Additional examples of chemotherapeutics include proteosome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Abl inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Flt-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic in the treatment of cancer, and mayimprove the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). In some embodiments, a corticosteroid such asdexamethasone is administered to a patient in combination with thecompounds of the disclosure where the dexamethasone is administeredintermittently as opposed to continuously.

In some embodiments, the compounds of the disclosure can be used incombination with an inhibitor of JAK or PI3Kδ. The agents can becombined with the present compound in a single or continuous dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab), 4-1BB (e.g. urelumab, utomilumab), antibodiesto PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.).Examples of antibodies to PD-1 and/or PD-L1 that can be combined withcompounds of the present disclosure for the treatment of cancer orinfections such as viral, bacteria, fungus and parasite infectionsinclude, but are not limited to nivolumab, pembrolizumab, atezolizumab,durvalumab, avelumab, cemiplimab, spartalizumab, camrelizumab,cetrelimab, toripalimab, sintilimab, AB122, AMP-224, JTX-4014, BGB-108,BCD-100, BAT1306, LZM009, AK105, HLX10, TSR-042, tislelizumab,BMS-935559, MEDI4736, FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167,STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, LY3300054, MCLA-136, andSHR-1210.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp 100, MAGEantigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected toexpress the cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

In some further embodiments, combinations of the compounds of thedisclosure with other therapeutic agents can be administered to apatient prior to, during, and/or after a bone marrow transplant or stemcell transplant. The compounds of the present disclosure can be used incombination with bone marrow transplant for the treatment of a varietyof tumors of hematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the disclosure can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated.

Administration may be topical (including transdermal, epidermal,ophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal orintranasal), oral, or parenteral. Parenteral administration includesintravenous, intraarterial, subcutaneous, intraperitoneal intramuscularor injection or infusion; or intracranial, e.g., intrathecal orintraventricular, administration. Parenteral administration can be inthe form of a single bolus dose, or may be, for example, by a continuousperfusion pump. Pharmaceutical compositions and formulations for topicaladministration may include transdermal patches, ointments, lotions,creams, gels, drops, suppositories, sprays, liquids and powders.Conventional pharmaceutical carriers, aqueous, powder or oily bases,thickeners and the like may be necessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the disclosure, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the disclosure may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the disclosure can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the disclosure can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the disclosure contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the disclosure.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials can be used for such entericlayers or coatings, such materials including a number of polymeric acidsand mixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentdisclosure can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the disclosure. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the disclosure in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of thedisclosure can be provided in an aqueous physiological buffer solutioncontaining about 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the disclosure can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present disclosure relates to labeled compounds ofthe disclosure (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating STING in tissue samples,including human, and for identifying STING activators by inhibitionbinding of a labeled compound. Substitution of one or more of the atomsof the compounds of the present disclosure can also be useful ingenerating differentiated ADME (Adsorption, Distribution, Metabolism andExcretion.) Accordingly, the present disclosure includes STING assaysthat contain such labeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas -CD₃ being substituted for —CH₃). In some embodiments, alkyl groupsin Formula (I) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. In some embodiments, the compound includes twoor more deuterium atoms. In some embodiments, the compound includes 1-2,1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of thehydrogen atoms in a compound can be replaced or substituted by deuteriumatoms.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of “alkyl”, “alkenyl”, “alkynyl”, “aryl”, “phenyl”,“cycloalkyl”, “heterocycloalkyl”, or “heteroaryl” substituents or “—C₁₋₆alkyl-”, “alkylene”, “alkenylene” and “alkynylene” linking groups, asdescribed herein, are optionally replaced by deuterium atoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro STING labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I or ³⁵S canbe useful. For radio-imaging applications C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I,¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the disclosure can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind activate STING by monitoring itsconcentration variation when contacting with STING, through tracking ofthe labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known tobind to STING (i.e., standard compound). Accordingly, the ability of atest compound to compete with the standard compound for binding to STINGdirectly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, forexample, in the treatment or prevention of STING-associated diseases ordisorders (such as, e.g., cancer, an inflammatory disease, acardiovascular disease, or a neurodegenerative disease) which includeone or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thedisclosure. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature (see e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004)). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity analysis under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm, 2.1×50 mm, Buffers: mobile phase A: 0.025% TFA in water and mobilephase B: acetonitrile; gradient 2% to 80% of B in 3 minutes with flowrate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm, 30×100 mm or WatersXBridge™ C₁₈ 5 μm, 30×100 mm column, eluting with mobile phase A: 0.1%TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile;the flow rate was 60 mL/minute, the separating gradient was optimizedfor each compound using the Compound Specific Method Optimizationprotocol as described in the literature (see e.g. “Preparative LCMSPurification: Improved Compound Specific Method Optimization”, K. Blom,B. Glass, R. Sparks, A. Combs, J Comb. Chem., 6, 874-883 (2004)).

pH=10 purifications: Waters XBridge™ C₁₈ 5 μm, 30×100 mm column, elutingwith mobile phase A: 0.1% NH₄OH in water and mobile phase B:acetonitrile; the flow rate was 60 mL/minute, the separating gradientwas optimized for each compound using the Compound Specific MethodOptimization protocol as described in the literature (see e.g.“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)).

Example 1.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1: 4-fluoro-3-methyl-5-nitrobenzamide

At 0° C., a mixture of nitric acid (2.51 ml, 39.2 mmol) and sulfuricacid (2.173 ml, 40.8 mmol) was added dropwise over 10 min into asolution of 4-fluoro-3-methylbenzamide (4.46 g, 29.1 mmol) in sulfuricacid (13.97 ml, 262 mmol). The mixture was stirred for 1.5 h whileslowly warming up to room temperature. The mixture was slowly pouredinto ice water (50 mL), and the precipitated solid was filtered and thenwashed with water (50 mL). The resulting solid residue was dried toprovide the desired product as a white solid. LC-MS calculated forC₈H₈FN₂O₃ (M+H)⁺: m/z=199.04; found 199.2.

Step 2: (E)-tert-butyl4-(4-carbamoyl-2-methyl-6-nitrophenylamino)but-2-enylcarbamate

To a solution of 4-fluoro-3-methyl-5-nitrobenzamide (0.400 g, 2.019mmol) and tert-butyl (E)-(4-aminobut-2-en-1-yl)carbamate (0.376 g, 2.019mmol) (Ark Pharm, cat #AK308564) in dry DMSO (2.019 ml) was added K₂CO₃(0.614 g, 4.44 mmol). The resulting yellow solution was stirred at roomtemperature for 1 h. The reaction mixture was diluted with water (15 mL)dropwise. The precipitated solid was filtered and then washed with water(10 mL). The resulting solid residue was dried to provide the desiredproduct as a yellow solid. LC-MS calculated for C₁₇H₂₄N₄NaO₅ (M+Na)⁺:m/z=387.2; found 387.2.

Step 3: (E)-tert-butyl4-(2-amino-4-carbamoyl-6-methylphenylamino)but-2-enylcarbamate

To a solution of tert-butyl(E)-(4-((4-carbamoyl-2-methyl-6-nitrophenyl)amino)but-2-en-1-yl)carbamate(220 mg, 0.604 mmol) in dioxane (1509 μl) and water (503 μl) was addedammonium chloride (226 mg, 4.23 mmol) and zinc (276 mg, 4.23 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 h, afterwhich time it was filtered through a Celite® bed. The filtrate waspartitioned between DCM and water. The organic layer was separated,dried over MgSO₄, filtered, and concentrated to provide the product.LC-MS calculated for C₁₇H₂₆N₄NaO₃ (M+Na)⁺: m/z=357.2; found 357.3.

Step 4: (E)-tert-butyl4-(2-amino-5-carbamoyl-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enylcarbamate

To a solution of tert-butyl(E)-(4-((2-amino-4-carbamoyl-6-methylphenyl)amino)but-2-en-1-yl)carbamate(0.201 g, 0.60 mmol) in MeOH (2.000 ml) was added cyanogen bromide(0.047 ml, 0.900 mmol). The reaction mixture was stirred at roomtemperature for 1 h. The mixture was diluted with DCM, and washed withwater and brine. The organic phase was dried over MgSO₄ beforefiltering. The filtrate was concentrated and purified by flashchromatography on a silica gel column eluting with 0 to 8% MeOH in DCMto afford the desired product. LC-MS calculated for C₁₈H₂₆N₅O₃ (M+H)⁺:m/z=360.2; found 360.3.

Step 5: (E)-tert-butyl4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enylcarbamate

A mixture of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid(Combi-Blocks, cat #QB-0979: 93 mg, 0.60 mmol), tert-butyl(E)-(4-(2-amino-5-carbamoyl-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate(216 mg, 0.600 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (274 mg, 0.720 mmol), andN,N-Diisopropylethylamine (209 μl, 1.200 mmol) in DMF (2000 μl) wasstirred at room temperature for 2 h. The mixture was concentrated underreduced pressure. The mixture was then diluted with DCM and water, andthe layers were separated. The aqueous layer was further extracted withDCM and the combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude residue waspurified by flash chromatography on a silica gel column eluting with 0to 8% MeOH in DCM to afford the desired product. LC-MS calculated forC₂₅H₃₄N₇O₄ (M+H)⁺: m/z=496.3; found 496.3.

Step 6:(E)-1-(4-aminobut-2-enyl)-2-(1-ethyl-3-methyl-1H-benzo[d]imidazole-5-carboxamide

To a solution of tert-butyl(E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate(180.0 mg, 0.363 mmol) in DCM (2.0 mL) was added TFA (0.2 mL). Theresulting solution was stirred at room temperature for 0.5 h. Thereaction mixture was quenched by NaHCO₃ aqueous solution then extractedwith DCM. The organic phases were combined and dried over MgSO₄, thenfiltered.

The filtrate was concentrated and used directly in the next step withoutfurther purification. For characterization purposes, the crude materialwas purified by prep HPLC (pH=2, water+TFA) to provide the desiredcompound as its TFA salt. LC-MS calculated for C₂₀H₂₆N₇O₂ (M+H)⁺:m/z=396.2; found 396.3. ¹H NMR (400 MHz, DMSO) δ 12.91 (s, 1H), 7.87 (m,2H), 7.69 (br s, 2H), 7.57 (s, 1H), 7.30 (s, 1H), 6.64 (s, 1H), 6.10(dt, J 16.0, 4.8 Hz, 1H), 5.33 (dt, J=16.0, 6.4 Hz, 1H), 5.06 (brs, 2H),4.59 (q, J=6.8 Hz, 2H), 3.42 (dt, J=6.4 Hz, 4.8 Hz, 2H), 2.63 (s, 3H),2.16 (s, 3H), 1.34 (t, J=6.8 Hz, 3H).

Step 7:(E)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-enyl)-7-methyl-1H-benzo[d]imidazole-5-carboxamide

To a mixture of(E)-1-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(180.0 mg, 0.455 mmol) and KBr (108 mg, 0.910 mmol) in water (228 μl)was added sodium nitrite (62.8 mg, 0.910 mmol). The mixture was stirredat 70° C. for 2 h. After cooling to rt, the mixture was diluted withDCM, and washed with water and brine. The organic phase was dried overMgSO₄ before filtering. The filtrate was concentrated to afford thedesired product. LC-MS calculated for C₂₀H₂₅N₆O₃ (M+H)⁺: m/z=397.2;found 397.2.

Step 8:(E)-1-(4-bromobut-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide

To a solution of(E)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-enyl)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(180.0 mg, 0.455 mmol) in THF (2.0 mL) was added PBr₃ (86 μl, 0.910mmol) dropwise. The resulting solution was stirred at room temperaturefor 10 h. The reaction mixture was quenched by NaHCO₃ aqueous solutionthen extracted with DCM. The organic phases were combined and dried overMgSO₄, then filtered.

The crude residue was purified by flash chromatography on a silica gelcolumn eluting with 0 to 10% MeOH in DCM to afford the desired product.LC-MS calculated for C₂₀H₂₄BrN₆O₂ (M+H)⁺: m/z=459.1, 461.1; found 459.1,461.1.

Step 9: 3-(2-chloropyrimidin-5-yl)-4-nitrobenzamide

To a solution of 3-bromo-4-nitrobenzamide (Matrix Scientific, cat#184225: 600.0 mg, 2.449 mmol), (2-chloropyrimidin-5-yl)boronic acid(Combi-Blocks, cat #BB-5457: 388 mg, 2.449 mmol), and sodium carbonate(519 mg, 4.90 mmol) in dioxane (2 mL) and water (0.4 mL) was addeddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (120 mg, 0.147 mmol). The vial was flushed withnitrogen, and the reaction was stirred at 100° C. for 1 h. The reactionmixture was quenched by NH₄OH aqueous solution then extracted with DCM.The organic phases were combined and dried over MgSO₄, then filtered.The crude residue was purified by flash chromatography on a silica gelcolumn eluting with 0 to 8% MeOH in DCM to afford the desired product.LC-MS calculated for C₁₁H₈ClN₄O₃ (M+H)⁺: m/z=279.0; found 279.0.

Step 10: 2-chloro-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of 3-(2-chloropyrimidin-5-yl)-4-nitrobenzamide (320.0 mg,1.148 mmol) and 1,2-bis(diphenylphosphino)ethane (572 mg, 1.435 mmol)was dissolved in 1,2-dichlorobenzene (3828 μl). The vial was flushedwith nitrogen before heating at 160° C. for 1 h. After removal of thesolvent under vacuum, the reaction mixture was extracted with DCM andwater. The organic phases were combined and dried over MgSO4, filtered,then concentrated under reduced pressure. The crude residue was purifiedby flash chromatography on a silica gel column eluting with 0 to 8% MeOHin DCM to afford the desired product. LC-MS calculated for C₁₁H₈ClN₄O(M+H)⁺: m/z=247.0; found 247.0.

Step 11:2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

To a solution of 2-chloro-9H-pyrimido[4,5-b]indole-6-carboxamide (60.0mg, 0.243 mmol),1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Enamine, cat #EN300-207291: 57.4 mg, 0.243 mmol), and sodium carbonate(51.6 mg, 0.487 mmol) in dioxane (676 μl) and water (135 μl) was addeddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (11.92 mg, 0.015 mmol). The vial was flushed withnitrogen, and the reaction was stirred at 100° C. for 1 h. The reactionmixture was quenched by NH₄OH aqueous solution then extracted with DCM.The organic phases were combined and dried over MgSO₄, then filtered.The crude residue was purified by flash chromatography on a silica gelcolumn eluting with 0 to 8% MeOH in DCM to afford the desired product.LC-MS calculated for C₁₇H₁₇N₆O (M+H)⁺: m/z=321.1; found 321.1.

Step 12:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(5.0 mg, 0.016 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(7.17 mg, 0.016 mmol), and cesium carbonate (11.19 mg, 0.034 mmol) wasstirred in DMF (156 μl) at 50° C. for 1 h. The reaction mixture wasdiluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₇H₃₉N₁₂O₃ (M+H)⁺: m/z=699.3; found 699.3.

Example 2.(E)-1-(4-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide

Step 1: 2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole

This compound was prepared using similar procedures as described forExample 1, Step 9 to Step 11 with 1-bromo-2-nitrobenzene (Aldrich, cat#365424) replacing 3-bromo-4-nitrobenzamide. LC-MS calculated forC₁₆H₁₆N₅ (M+H)⁺: m/z=278.2; found 278.2.

Step 2:(E)-1-(4-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide

A mixture of2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole (5.0 mg,0.018 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(8.28 mg, 0.018 mmol), and cesium carbonate (12.92 mg, 0.040 mmol) wasstirred in DMF (60.1 μl) at 50° C. for 1 h. The reaction mixture wasdiluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₆H₃₈N₁₁O₂ (M+H)⁺: m/z=656.3; found 656.3.

Example 3.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1,3-dimethyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1:2-(1,3-dimethyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 11 with1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Combi-Blocks, cat #PN-6021) replacing1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LC-MS calculated for C₁₆H₁₅N₆O (M+H)⁺: m/z=307.2; found 307.2.

Step 2:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1,3-dimethyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of2-(1,3-dimethyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(5.0 mg, 0.016 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(7.50 mg, 0.016 mmol), and cesium carbonate (11.70 mg, 0.036 mmol) wasstirred in DMF (54.4 μl) at 50° C. for 1 h. The reaction mixture wasdiluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₆H₃₇N₁₂O₃ (M+H)⁺: m/z=685.3; found 685.3. ¹H NMR(600 MHz, DMSO) δ 9.50 (s, 1H), 8.81 (s, 1H), 8.05 (d, J=8.6 Hz, 1H),7.83 (s, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.46 (s, 1H), 6.79 (s, 1H), 6.45(s, 1H), 5.91 (dt, J=15.6, 4.8 Hz, 1H), 5.66 (dt, J=15.6, 4.8 Hz, 1H),5.13 (d, J=4.8 Hz, 2H), 4.95 (d, J=4.8 Hz, 2H), 4.49 (q, J=7.0 Hz, 3H),4.17 (s, 3H), 2.46 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.24 (t, J=7.0Hz, 2H).

Example 4.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1: 4-fluoro-3-methoxy-5-nitrobenzamide

Methyl 4-fluoro-3-methoxy-5-nitrobenzoate (4.0 g, 17.45 mmol) wasstirred in ammonium hydroxide (42.8 ml, 1100 mmol) at room temperaturefor 10 h. The solid was filtered and rinsed with cold water. Theresulting solid residue was dried to provide the desired product as alight yellow solid. LC-MS calculated for C₈H₈FN₂O₄ (M+H)⁺: m/z=215.04;found 215.2.

Step 2: (E)-tert-butyl4-(4-carbamoyl-2-methoxy-6-nitrophenylamino)but-2-enylcarbamate

To a solution of 4-fluoro-3-methoxy-5-nitrobenzamide (300.0 mg, 1.401mmol), tert-butyl (E)-(4-aminobut-2-en-1-yl)carbamate (391 mg, 2.101mmol) in dry DMSO (2335 μl) was added K₂CO₃ (387 mg, 2.80 mmol). Theresulting solution was heated at 70° C. for 12 h. The mixture wasconcentrated under reduced pressure, and then extracted with DCM andwater. The combined organic layers were dried, filtered, andconcentrated in vacuo. The crude residue was purified by flashchromatography on a silica gel column to afford the desired product.LC-MS calculated for C₁₇H₂₄N₄NaO₆ (M+Na)⁺: m/z=403.2; found 403.2.

Step 3:(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 3-8 with (E)-tert-butyl4-(4-carbamoyl-2-methoxy-6-nitrophenylamino)but-2-enylcarbamatereplacing(E)-(4-((4-carbamoyl-2-methyl-6-nitrophenyl)amino)but-2-en-1-yl)carbamate.LC-MS calculated for C₂₀H₂₄BrN₆O₃ (M+H)⁺: m/z=475.1, 477.1; found 475.1,477.1.

Step 4:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(5.0 mg, 0.016 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide(7.42 mg, 0.016 mmol), and cesium carbonate (11.19 mg, 0.034 mmol) wasstirred in DMF (52.0 μl) at 50° C. for 1 h. The reaction mixture wasdiluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₇H₃₉N₁₂O₄ (M+H)⁺: m/z=715.3; found 715.3.

Example 5.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamide

Step 1:3-(6-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyridin-3-yl)-4-nitrobenzonitrile

To a degasseed solution of 3-bromo-4-nitrobenzonitrile (J& W PharmLab,cat #05R0293: 50 mg, 0.220 mmol) and2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Aldrich, cat #659843: 52.8 mg, 0.220 mmol) in dioxane (587 μl) andwater (147 μl) was addeddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (8.99 mg, 0.011 mmol) and sodium carbonate (46.7mg, 0.440 mmol). The reaction was stirred at 100° C. for 2 h.1-Ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Enamine Ltd, cat #EN300-207291: 52.0 mg, 0.220 mmol) was added. Thereaction mixture was heated to 100° C. for another 1 h. H₂O (2 mL) wasadded to the reaction mixture, followed by extraction with ethyl acetate(2 mL×5). The combined organic layers were dried with Na₂SO₄, filteredand concentrated. The crude product was used directly without furtherpurification. LC-MS calculated for C₁₈H₁₆N₅O₂ (M+H)⁺: m/z=334.1; found334.2.

Step 2:2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carbonitrile

To a solution of above crude3-(6-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyridin-3-yl)-4-nitrobenzonitrilein 1,2-dichlorobenzene (1 mL) was added dppe (132 mg, 0.330 mmol). Thereaction mixture was heated to 160° C. for 3 h, then the solvent wasremoved under vacuum. The crude product was used directly withoutfurther purification. LC-MS calculated for C₁₈H₁₆N₅ (M+H)⁺: m/z=302.1;found 302.2.

Step 3:2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamide

The above crude2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carbonitrilewas dissolved in EtOH (0.8 mL) and water (0.2 mL). Ghaffar-Parkins cat.(5 mg) was added and the resulting mixture was heated at 95° C. for 4 hto afford2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamideas the major regioselective isomer. The reaction mixture was dilutedwith MeOH then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated for C₁₈H₁₈N₅O(M+H)⁺: m/z=320.1; found 320.2. ¹H NMR (500 MHz, DMSO-d6) δ 12.13 (s,1H), 8.75 (s, 1H), 8.57 (d, J=8.0 Hz, 1H), 8.01 (dd, J=8.5, 1.6 Hz, 2H),7.97-7.93 (m, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H),7.37-7.15 (m, 1H), 6.58 (s, 1H), 4.64 (q, J=7.1 Hz, 2H), 2.21 (s, 3H),1.37 (t, J=7.1 Hz, 3H).

Step 4:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamide

A mixture of2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamide(3.5 mg, 0.011 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(5.0 mg, 0.011 mmol), and cesium carbonate (12.92 mg, 0.040 mmol) wasstirred in DMF (60.1 μl) at r.t. for 1 h. The reaction mixture wasdiluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₈H₄₀N₁₁O₃ (M+H)⁺: m/z=698.3; found 698.3.

Example 6.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1:2-(3-methyl-1-propyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 11 with3-methyl-1-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Combi-Blocks, cat #FM-3989) replacing1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LC-MS calculated for C₁₈H₁₉N₆O (M+H)⁺: m/z=335.2; found 335.2.

Step 2:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of2-(3-methyl-1-propyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(6.68 mg, 0.02 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(Example 1, Step 8; 9.18 mg, 0.02 mmol), and cesium carbonate (14.32 mg,0.040 mmol) was stirred in DMF (0.2 mL) at 50° C. for 1 h. The reactionmixture was diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₈H₄₁N₁₂O₃ (M+H)⁺: m/z=713.3; found 713.4.

Example 7.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1:2-(1-ethyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 11 with1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Combi-Blocks, cat #PN-6476) replacing1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LC-MS calculated for C₁₆H₁₅N₆O (M+H)⁺: m/z=307.1; found 307.1.

Step 2:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of2-(1-ethyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide (6.12mg, 0.02 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(Example 1, Step 8: 9.18 mg, 0.02 mmol), and cesium carbonate (14.32 mg,0.044 mmol) was stirred in DMF (0.2 mL) at 50° C. for 1 h. The reactionmixture was diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₆H₃₇N₁₂O₃ (M+H)⁺: m/z=685.3; found 685.4.

Example 8.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1:2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 11 with3-ethyl-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(AstaTech, cat #P 17340) replacing1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LC-MS calculated for C₁₇H₁₇N₆O (M+H)⁺: m/z=321.1; found 321.1.

Step 2:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(6.4 mg, 0.02 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(Example 1, Step 8: 9.18 mg, 0.02 mmol), and cesium carbonate (14.32 mg,0.044 mmol) was stirred in DMF (0.2 mL) at 50° C. for 1 h. The reactionmixture was diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₇H₃₉N₁₂O₃ (M+H)⁺: m/z=699.3; found 699.4.

Example 9.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1:2-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 11 with1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazolereplacing1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LC-MS calculated for C₁₇H₁₄F₃N₆O (M+H)⁺: m/z=375.1; found 375.1.

Step 2:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of2-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(8.96 mg, 0.024 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(Example 1, Step 8: 11 mg, 0.024 mmol), and cesium carbonate (17.2 mg,0.053 mmol) was stirred in DMF (0.2 mL) at 50° C. for 1 h. The reactionmixture was diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₇H₃₆F₃N₁₂O₃ (M+H)⁺: m/z=753.3; found 753.4.

Example 10.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1: 3-bromo-5-fluoro-4-nitrobenzamide

Methyl 3-bromo-5-fluoro-4-nitrobenzoate (AstaTech, cat #AB9640: 5.0 g,17.98 mmol) was stirred in ammonium hydroxide (44.1 ml, 1133 mmol) atroom temperature for 10 h. The solid was filtered and rinsed with coldwater. The resulting solid residue was dried to provide the desiredproduct as a light yellow solid.

Step 2: 3-bromo-5-methoxy-4-nitrobenzamide

To a stirred solution of 3-bromo-5-fluoro-4-nitrobenzamide (1.0 g, 3.80mmol) in MeOH (19.01 ml) was added sodium methoxide (1.232 g, 5.70mmol). The reaction mixture was stirred at 60° C. for 0.5 h. Thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in water, and then extracted with DCM. The combinedorganic layers were dried, filtered, and concentrated in vacuo. Thecrude product was used directly without further purification. LC-MScalculated for C₈H₈BrN₂O₄ (M+H)⁺: m/z=275.0, 277.0; found 275.0, 277.0.

Step 3:3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide

To a degassed solution of (2-chloropyrimidin-5-yl)boronic acid(Combi-Blocks, cat #BB-5457: 82 mg, 0.52 mmol) and3-bromo-5-methoxy-4-nitrobenzamide (143 mg, 0.520 mmol) in dioxane (1733μl) and water (347 μl) was addeddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (25.5 mg, 0.031 mmol) and sodium carbonate (110mg, 1.040 mmol). The reaction was stirred at 100° C. for 2 h. Then,1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Enamine Ltd, cat #EN300-207291; 123.0 mg, 0.520 mmol) was added. Thereaction mixture was heated to 100° C. for another 1 h. H₂O was added tothe reaction mixture, and the reaction was extracted with DCM. Thecombined organic layers were dried with Na₂SO₄, filtered andconcentrated. The crude residue was purified by flash chromatography ona silica gel column eluting with 0 to 8% MeOH in DCM to afford thedesired product. LC-MS calculated for C₁₈H₁₉N₆O₄ (M+H)⁺: m/z=383.1;found 383.2.

Step 4:2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide(280.0 mg, 0.732 mmol) and 1,2-bis(diphenylphosphino)ethane (365 mg,0.915 mmol) was dissolved in 1,2-dichlorobenzene (2.4 mL). The vial wasflushed with nitrogen before heating at 160° C. for 1 h. After removalof the solvent under vacuum, the reaction mixture was extracted with DCMand water. The organic phases were combined and dried over MgSO₄,filtered, then concentrated under reduced pressure. The crude residuewas purified by flash chromatography on a silica gel column eluting with0 to 8% MeOH in DCM to afford the desired product. LC-MS calculated forC₁₈H₁₉N₆O₂ (M+H)⁺: m/z=351.1; found 351.1.

Step 5:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide(7.0 mg, 0.02 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(Example 1, Step 8; 9.18 mg, 0.02 mmol), and cesium carbonate (14.32 mg,0.044 mmol) was stirred in DMF (0.2 mL) at 50° C. for 1 h. The reactionmixture was diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₈H₄₁N₁₂O₄ (M+H)⁺: m/z=729.3; found 729.4.

Example 11.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1: 3-bromo-5-(3-morpholinopropoxy)-4-nitrobenzamide

To a stirred solution of 3-morpholinopropan-1-ol (Combi-Blocks, cat#OR-5079: 0.121 g, 0.836 mmol) in THF (2.79 ml) was added sodium hydride(0.067 g, 1.673 mmol). The reaction mixture was stirred at roomtemperature for 10 min. To the solution of sodium alkoxide was thenadded 3-bromo-5-fluoro-4-nitrobenzamide (0.220 g, 0.836 mmol). Themixture was heated at 60° C. for 0.5 h. The reaction mixture wasconcentrated under reduced pressure, and then extracted with DCM andwater. The combined organic layers were dried, filtered, andconcentrated in vacuo. The crude product was used directly withoutfurther purification. LC-MS calculated for C₁₄H₁₉BrN₃O₅ (M+H)⁺:m/z=388.0, 390.0; found 388.1, 390.1.

Step 2:3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-(3-morpholinopropoxy)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 10, Step 3 with 3-bromo-5-(3-morpholinopropoxy)-4-nitrobenzamidereplacing 3-bromo-5-methoxy-4-nitrobenzamide. LC-MS calculated forC₂₄H₃₀N₇O₅ (M+H)⁺: m/z=496.2; found 496.3.

Step 3:2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 10, Step 4 with3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-(3-morpholinopropoxy)-4-nitrobenzamidereplacing3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide.LC-MS calculated for C₂₄H₃₀N₇O₃ (M+H)⁺: m/z=464.2; found 464.3.

Step 4:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(7.0 mg, 0.015 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(Example 1, Step 8; 6.94 mg, 0.015 mmol), and cesium carbonate (10.82mg, 0.033 mmol) was stirred in DMF (0.2 mL) at 50° C. for 1 h. Thereaction mixture was diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₄₄H₅₂N₁₃O₅ (M+H)⁺: m/z=842.4; found 842.4.

Example 12.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1: 3-bromo-5-(3-methoxypropoxy)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 11, Step 1 with 3-methoxypropan-1-ol (Aldrich, cat #38457)replacing 3-morpholinopropan-1-ol. LC-MS calculated for C₁₁H₁₄BrN₂O₅(M+H)⁺: m/z=333.0, 335.0; found 333.0, 335.0.

Step 2:3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-(3-methoxypropoxy)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 10, Step 3 with 3-bromo-5-(3-methoxypropoxy)-4-nitrobenzamidereplacing 3-bromo-5-methoxy-4-nitrobenzamide. LC-MS calculated forC₂₁H₂₅N₆O₅ (M+H)⁺: m/z=441.2; found 441.3.

Step 3:2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 10, Step 4 with3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-(3-methoxypropoxy)-4-nitrobenzamidereplacing3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide.LC-MS calculated for C₂₁H₂₅N₆O₃ (M+H)⁺: m/z=409.2; found 409.2.

Step 4:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(7.0 mg, 0.015 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(Example 1, Step 8: 6.94 mg, 0.015 mmol), and cesium carbonate (10.82mg, 0.033 mmol) was stirred in DMF (0.2 mL) at 50° C. for 1 h. Thereaction mixture was diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₄₁H₄₇N₁₂O₅ (M+H)⁺: m/z=787.4; found 787.4.

Example 13.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-hydroxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1:3-bromo-5-(3-(tert-butyldimethylsilyloxy)propoxy)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 11, Step 1 with 3-((tert-butyldimethylsilyl)oxy)propan-1-ol(Combi-Blocks, cat #QH-3826) replacing 3-morpholinopropan-1-ol. LC-MScalculated for C₁₆H₂₆BrN₂O₅Si (M+H)⁺: m/z=433.1, 435.1; found 433.2,435.2.

Step 2:3-(3-(tert-butyldimethylsilyloxy)propoxy)-5-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 10, Step 3 with3-bromo-5-(3-(tert-butyldimethylsilyloxy)propoxy)-4-nitrobenzamidereplacing 3-bromo-5-methoxy-4-nitrobenzamide. LC-MS calculated forC₂₆H₃₇N₆O₅Si (M+H)⁺: m/z=541.3; found 541.3.

Step 3:8-(3-(tert-butyldimethylsilyloxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 10, Step 4 with3-(3-(tert-butyldimethylsilyloxy)propoxy)-5-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-4-nitrobenzamidereplacing3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide.LC-MS calculated for C₂₆H₃₇N₆O₃Si (M+H)⁺: m/z=509.3; found 509.3.

Step 4:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-hydroxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

A mixture of28-(3-(tert-butyldimethylsilyloxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(7.63 mg, 0.015 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(6.89 mg, 0.015 mmol), and cesium carbonate (10.75 mg, 0.033 mmol) wasstirred in DMF (0.2 mL) at 50° C. for 1 h. The primary alcohol wasdeprotected during the process. Otherwise, the TBS group could beremoved with the addition of 4 equivalents of HCl (0.015 mL of 4 M HClin dioxane), followed by stirring at room temperature for 1 h. Thereaction mixture was diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₄₀H₄₅N₁₂O₅ (M+H)⁺: m/z=773.4; found 773.4.

Example 14.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrido[2,3-b]indole-6-carboxamide

Step 1:3-(6-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyridin-3-yl)-5-methoxy-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 10, Step 3 with2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinereplacing (2-chloropyrimidin-5-yl)boronic acid. LC-MS calculated forC₁₉H₂₀N₅O₄ (M+H)⁺: m/z=382.1; found 382.3.

Step 2:2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrido[2,3-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 10, Step 4 with3-(6-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyridin-3-yl)-5-methoxy-4-nitrobenzamidereplacing3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide.Two isomers were formed. The reaction mixture was diluted with MeOH andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as its TFA salt. LC-MS calculated for C₁₉H₂₀N₅O₂ (M+H)⁺:m/z=350.2; found 350.2. ¹H NMR (500 MHz, DMSO) δ 12.26 (s, 1H), 8.53 (d,J=8.1 Hz, 1H), 8.39 (s, 1H), 7.59 (s, 1H), 7.57 (d, J=8.1 Hz, 1H), 6.58(s, 1H), 4.65 (q, J=7.1 Hz, 2H), 4.04 (s, 3H), 2.21 (s, 3H), 1.36 (t,J=7.1 Hz, 3H).

Step 3:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrido[2,3-b]indole-6-carboxamide

A mixture of2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrido[2,3-b]indole-6-carboxamide(7.0 mg, 0.02 mmol),(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(9.18 mg, 0.02 mmol), and cesium carbonate (14.32 mg, 0.044 mmol) wasstirred in DMF (0.2 mL) at 50° C. for 1 h. The reaction mixture wasdiluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₃₉H₄₂N₁₁O₄ (M+H)⁺: m/z=728.3; found 728.4.

Example 15.(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

Step 1: 4-chloro-3-hydroxy-5-nitrobenzamide

In a round-bottomed flask, 4-chloro-3-methoxy-5-nitrobenzamide(Astatech, cat #97780: 1.0 g, 4.34 mmol) was dissolved in DCM. 1M BBr₃in DCM (13.01 ml, 13.01 mmol) was added to the reaction mixturedropwise, then was refluxed for 12 h. The reaction mixture was cooledand then was poured into ice water. After stirring for 30 min, thereaction mixture was filtered and the filter cake was rinsed with waterand dried to provide the desired compound as a white solid. LC-MScalculated for C₇H₆ClN₂O₄ (M+H)⁺: m/z=217.0; found 216.9.

Step 2:3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-chloro-5-nitrobenzamide

To a suspension of 4-chloro-3-hydroxy-5-nitrobenzamide (211.0 mg, 0.974mmol), and cesium carbonate (476 mg, 1.461 mmol) in DMF (3247 μl) wasadded (3-bromopropoxy)(tert-butyl)dimethylsilane (Aldrich, cat #429066:271 μl, 1.169 mmol). The reaction was then sealed and heated to 50° C.with stirring for 12 h. After cooling with an ice bath, the product wastriturated with cold water, filtered, and dried to provide the desiredproduct as a yellow solid. LC-MS calculated for C₁₆H₂₆ClN₂O₅Si (M+H)⁺:m/z=389.1; found 389.1.

Step 3: tert-butyl(E)-(4-((2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoyl-6-nitrophenyl)amino)but-2-en-1-yl)carbamate

To a vial was added3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-chloro-5-nitrobenzamide(1.004 g, 2.58 mmol), tert-butyl (E)-(4-aminobut-2-en-1-yl)carbamate(Ark Pharm, cat #AK308564: 0.481 g, 2.58 mmol), DMSO (12.91 ml), andDIPEA (2.254 ml, 12.91 mmol). The mixture was sealed, then heated at100° C. overnight with stirring. After cooling to rt, the mixture wasdiluted with water and extracted with CHCl₃/IPA (3:1). The combinedorganic extracts were dried over MgSO₄, filtered, and concentrated invacuo to provide the desired product as a brown oil. LC-MS calculatedfor C₂₅H₄₃N₄O₇Si (M+Na)⁺: m/z=561.3; found 561.3.

Step 4: tert-butyl(E)-(4-((2-amino-6-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoylphenyl)amino)but-2-en-1-yl)carbamate

This compound was prepared using similar procedures as described forExample 1, Step 3 with tert-butyl(E)-(4-((2-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoyl-6-nitrophenyl)amino)but-2-en-1-yl)carbamatereplacing tert-butyl(E)-(4-((4-carbamoyl-2-methyl-6-nitrophenyl)amino)but-2-en-1-yl)carbamate.LC-MS calculated for C₂₅H₄₅N₄O₅Si (M+H)⁺: m/z=509.3; found 509.3.

Step 5: tert-butyl(E)-(4-(2-amino-5-carbamoyl-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate

This compound was prepared using similar procedures as described forExample 1, Step 4 with tert-butyl(E)-(4-((2-amino-6-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoylphenyl)amino)but-2-en-1-yl)carbamatereplacing tert-butyl(E)-(4-((2-amino-4-carbamoyl-6-methylphenyl)amino)but-2-en-1-yl)carbamate.LC-MS calculated for C₂₀H₃₀N₅O₅ (M+H)⁺: m/z=420.2; found 420.3.

Step 6:(E)-3-((1-(4-((tert-butoxycarbonyl)amino)but-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

To a solution of 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid(Combi-Blocks, cat #QB-0979: 0.336 g, 2.179 mmol) in DMF (4.95 ml) at rtwas added HATU (0.911 g, 2.397 mmol) and DIPEA (0.951 ml, 5.45 mmol).The mixture was stirred for 15 min, then a solution of tert-butyl(E)-(4-(2-amino-5-carbamoyl-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate(0.457 g, 1.089 mmol) in DMF (0.495 ml) was added and stirred overnight.The reaction was concentrated, and was diluted with water. The aqueousmixture was extracted with DCM (3×20 mL). The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated.The product was purified by column chromatography (15% MeOH/DCM) toprovide the desired product as a white solid. LC-MS calculated forC₃₄H₄₆N₉O₇ (M+H)⁺: m/z=692.3; found 692.4.

Step 7:(E)-3-((1-(4-aminobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 1, Step 6 with(E)-3-((1-(4-((tert-butoxycarbonyl)amino)but-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing tert-butyl(E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate.LC-MS calculated for C₂₉H₃₈N₉O₅ (M+H)⁺: m/z=592.3; found 592.4.

Step 8:(E)-3-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl 3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 1, Step 7 with(E)-3-((1-(4-aminobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing(E)-1-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide.LC-MS calculated for C₂₉H₃₇N₈O₆ (M+H)⁺: m/z=593.3; found 593.4.

Step 9:(E)-3-((1-(4-bromobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 1, Step 8 with(E)-3-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing(E)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-enyl)-7-methyl-1H-benzo[d]imidazole-5-carboxamide.LC-MS calculated for C₂₉H₃₆BrN₈O₅ (M+H)⁺: m/z=655.2/657.2; found655.3/657.3.

Step 10:(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

To a mixture of(E)-3-((1-(4-bromobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (24 mg, 0.037 mmol) and2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 10, Step 4: 12.83 mg, 0.037 mmol) in DMF (366 μl) was addedDIPEA (19.18 μl, 0.110 mmol). After stirring for 20 min, Cs₂CO₃ (35.8mg, 0.110 mmol) was added. The mixture was stirred at rt overnight. 180uL of the reaction mixture was removed and diluted with TFA/water, thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₄₇H₅₄N₁₄O₇(M+2H)²⁺:m/z=463.2; found 463.3.

Example 16.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide

To a mixture of(E)-3-((1-(4-bromobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (Example 15, Step 9: 24 mg,0.037 mmol) and2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 10, Step 4: 12.83 mg, 0.037 mmol) in DMF (366 μl) was addedDIPEA (19.18 μl, 0.110 mmol). After 20 min, Cs₂CO₃ (35.8 mg, 0.110 mmol)was added. The mixture was stirred at rt overnight. 180 uL of thereaction mixture was removed and purified to provide Example 15. To theremaining reaction mixture was added aqueous 1 N sodium hydroxide (36.6μl, 0.037 mmol). The mixture was stirred for 15 min, then was dilutedwith MeCN, TFA, then water. The resulting solution was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₄₀H₄₅N₁₂O₆ (M+H)⁺: m/z=789.4; found789.3.

Example 17.(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 15, Step 10 with2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 1, Step 11) replacing2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide.An aliquot of the reaction mixture was diluted with TFA/water, thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₄₆H₅₁N₁₄O₆ (M+H)⁺:m/z=895.4; found 895.4.

Example 18.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 16 with2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 1, Step 11) replacing2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide.The reaction mixture was diluted with TFA/water, then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₃₉H₄₃N₁₂O₅ (M+H)⁺: m/z=759.3; found759.3.

Example 19.(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 15, Step 10 with2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 11, Step 3) replacing2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide.An aliquot of the reaction mixture was diluted with TFA/water, thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₅₃H₆₅N₁₅O₈ (M+2H)²⁺:m/z=519.8; found 519.9.

Example 20.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indole-6-arboxamide

This compound was prepared using similar procedures as described forExample 16 with2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 11, Step 3) replacing2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide.The reaction mixture was diluted with TFA/water, then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₄₆H₅₇N₁₃O₇ (M+H)²⁺: m/z=451.7; found451.8.

Example 21.(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 15, Step 10 with2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 12, Step 3) replacing2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide.An aliquot of the reaction mixture was diluted with TFA/water, thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₅₀H₆₀N₁₄O₈(M+2H)²⁺:m/z=492.2; found 492.3.

Example 22.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 16 with2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 12, Step 3) replacing2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide.The remaining reaction mixture was diluted with TFA/water, then purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas the TFA salt. LC-MS calculated for C₄₃H₅₁N₁₂O₇ (M+H)⁺: m/z=847.4;found 847.4.

Example 23.(E)-5-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-4-fluoro-5H-pyrido[4,3-b]indole-8-carboxamide

Step 1: 3-(6-chloro-5-fluoropyridin-3-yl)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 1, Step 9 with2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Astatech, cat #33955) replacing (2-chloropyrimidin-5-yl)boronic acid.LC-MS calculated for C₁₂H₈ClFN₃O₃ (M+H)⁺: m/z=296.0; found 296.1.

Step 2:3-(6-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 1, Step 11 with3-(6-chloro-5-fluoropyridin-3-yl)-4-nitrobenzamide replacing2-chloro-9H-pyrimido[4,5-b]indole-6-carboxamide. LC-MS calculated forC₁₈H₁₇FN₅O₃ (M+H)⁺: m/z=370.1; found 370.1.

Step 3:3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-4-fluoro-5H-pyrido[4,3-b]indole-8-carboxamideand2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 10 with3-(6-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-5-fluoropyridin-3-yl)-4-nitrobenzamidereplacing 3-(2-chloropyrimidin-5-yl)-4-nitrobenzamide. After cooling tort, the reaction was concentrated under reduced pressure and purified byflash chromatography (15% MeOH/DCM) with2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indole-6-carboxamideeluting first (major product) and3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-4-fluoro-5H-pyrido[4,3-b]indole-8-carboxamideeluting second (minor product). LC-MS calculated for C₁₈H₁₇FN₅O (M+H)⁺:m/z=338.1; found 338.2. Major product: ¹H NMR (400 MHz, MeOD) δ 8.69 (s,1H), 8.37 (d, J=10.5 Hz, 1H), 8.05 (dd, J=8.6, 1.6 Hz, 1H), 7.56 (d,J=8.6 Hz, 1H), 6.56 (d, J=4.0 Hz, 1H), 4.56 (q, J=7.1 Hz, 2H), 3.35 (s,2H), 2.32 (s, 3H), 1.44 (t, J=7.1 Hz, 3H). Minor product: ¹H NMR (400MHz, MeOD) δ 9.22 (s, 1H), 8.81 (s, 1H), 8.11 (dd, J=8.6, 1.4 Hz, 1H),7.65 (d, J=8.6 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H),2.33 (s, 3H), 1.36 (t, J=7.1 Hz, 3H).

Step 4:(E)-5-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-3-(1-ethyl-3-methyl-H-pyrazol-5-yl)-4-fluoro-5H-pyrido[4,3-b]indole-8-carboxamide

To a mixture of(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide(Example 1, Step 8:10 mg, 0.022 mmol) and3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-4-fluoro-5H-pyrido[4,3-b]indole-8-carboxamide(7.34 mg, 0.022 mmol) in DMF (218 μl) was added DIPEA (11.41 μl, 0.065mmol). After 20 min, Cs₂CO₃ (21.28 mg, 0.065 mmol) was added. Themixture was stirred at rt overnight. The reaction was diluted withTFA/water, then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated forC₃₈H₃₉FN₁₁O₃ (M+H)⁺: m/z=716.3; found 716.3.

Example 24.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 23, Step 4 with2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indole-6-carboxamide(Example 23, Step 3) replacing3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-4-fluoro-5H-pyrido[4,3-b]indole-8-carboxamide.LC-MS calculated for C₃₈H₃₉FN₁₁O₃ (M+H)⁺: m/z=716.3; found 716.3.

Example 25.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-3-cyano-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamide

Step 1: (6-chloro-5-cyanopyridin-3-yl)boronic Acid

To a vial was added 5-bromo-2-chloronicotinonitrile (Aldrich, cat#759716: 0.500 g, 2.299 mmol), bis(pinacolato)diboron (0.701 g, 2.76mmol), potassium acetate (0.564 g, 5.75 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.188 g, 0.230 mmol), 1,4-dioxane (5.75 ml), anda stir bar. The mixture was sparged with nitrogen for 2 min, then wassealed and heated at 110° C. for 1 h with stirring. After cooling, themixture was filtered through Celite® and purified using flashchromatography (5% MeOH/DCM). LC-MS calculated for C₆H₅BClN₂O₂ (M+H)⁺:m/z=183.0; found 183.0.

Step 2: 3-(6-chloro-5-cyanopyridin-3-yl)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 1, Step 9 with (6-chloro-5-cyanopyridin-3-yl)boronic acidreplacing (2-chloropyrimidin-5-yl)boronic acid. LC-MS calculated forC₁₃H₈ClN₄O₃ (M+H)⁺: m/z=303.0; found 302.8.

Step 3:3-(5-cyano-6-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyridin-3-yl)-4-nitrobenzamide

This compound was prepared using similar procedures as described forExample 1, Step 11 with3-(6-chloro-5-cyanopyridin-3-yl)-4-nitrobenzamide replacing2-chloro-9H-pyrimido[4,5-b]indole-6-carboxamide. LC-MS calculated forC₁₉H₁₇N₆O₃ (M+H)⁺: m/z=377.1; found 377.1.

Step 4:3-cyano-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamideand 4-cyano-3-(1-ethyl-3-methyl-1H-pyrazol-5yl)-5H-pyrido[4,3-b]indole-8-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 10 with3-(5-cyano-6-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyridin-3-yl)-4-nitrobenzamidereplacing 3-(2-chloropyrimidin-5-yl)-4-nitrobenzamide. After cooling tort, the reaction was concentrated under reduced pressure and purified byflash chromatography (15% MeOH/DCM) with3-cyano-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamideeluting first (major product) and4-cyano-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-5H-pyrido[4,3-b]indole-8-carboxamideeluting second (minor product). LC-MS calculated for C₁₉H₁₇N₆O (M+H)⁺:m/z=345.1; found 345.2.

Step 5:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-3-cyano-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 23, Step 4 with3-cyano-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamidereplacing3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-4-fluoro-5H-pyrido[4,3-b]indole-8-carboxamide.¹H NMR (600 MHz, DMSO) δ 12.82 (s, 1H), 9.18 (s, 1H), 8.87 (s, 1H),8.15-8.07 (m, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 7.77 (d,J=8.6 Hz, 1H), 7.46 (s, 1H), 7.39 (s, 1H), 7.27 (s, 1H), 6.65 (s, 1H),6.41 (s, 1H), 5.84 (dt, J=15.6, 4.8 Hz, 1H), 5.55 (dt, J=15.6, 5.4 Hz,1H), 5.14 (d, J=4.8 Hz, 2H), 4.91 (brs, 2H), 4.46 (q, J=6.6 Hz, 2H),4.11 (q, J=7.2 Hz, 2H), 2.42 (s, 3H), 2.24 (s, 3H), 2.10 (s, 3H), 1.21(t, J=7.2 Hz, 3H), 1.17 (t, J=6.6 Hz, 3H). LC-MS calculated forC₃₉H₃₉N₁₂O₃ (M+H)⁺: m/z=723.3; found 723.3.

Example 26.(E)-5-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-cyano-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-5H-pyrido[4,3-b]indole-8-carboxamide

This compound was prepared using similar procedures as described forExample 23, Step 4 with4-cyano-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-5H-pyrido[4,3-b]indole-8-carboxamide(Example 25, Step 4) replacing3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-4-fluoro-5H-pyrido[4,3-b]indole-8-carboxamide.LC-MS calculated for C₃₉H₃₉N₁₂O₃ (M+H)⁺: m/z=723.3; found 723.3.

Example 27.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-oxopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

To a vial was added(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 22: 0.025 g, 0.030 mmol), DMF (0.295 ml), and a stir bar. Themixture was cooled to 0° C., and DMP (0.025 g, 0.059 mmol) and water(4.25 μl, 0.236 mmol) were added. The reaction was gradually warmed upto rt, stirring overnight. After cooling to 0° C., ice and sodiumbicarbonate were added, followed by saturated aqueous sodiumthiosulfate. The reaction was extracted with chloroform/ipa (3:1), driedover MgSO₄, filtered, and concentrated under reduced pressure. The crudeproduct was used directly in the next step without further purification.LC-MS calculated for C₄₃H₄₉N₁₂O₇ (M+H)⁺: m/z=845.4; found 845.3.

Step 2:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

To a vial was added(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-oxopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(0.025 g, 0.030 mmol), DMF (0.592 ml), DIPEA (0.016 ml, 0.089 mmol), andmorpholine (7.73 μl, 0.089 mmol). Sodium cyanoborohydride (5.58 mg,0.089 mmol) was then added and the reaction was stirred for 1 h. Thereaction was diluted with TFA/water, then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₄₇H₅₉N₁₃O₇(M+2H)²⁺: m/z=458.7; found 458.7.

Example 28.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-hydroxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared as a by-product from Example 27, Step 2,where-in(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-oxopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamideundergoes a retro-Michael reaction. The reaction was diluted withTFA/water, then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. ¹H NMR (600 MHz, DMSO) δ 12.67(s, 1H), 10.34 (s, 1H), 9.48 (s, 1H), 8.42 (d, J=1.2 Hz, 1H), 8.04 (s,1H), 7.78 (s, 1H), 7.60 (d, J=1.2 Hz, 1H), 7.41 (s, 1H), 7.36 (s, 1H),7.19 (s, 1H), 7.10 (s, 1H), 6.79 (s, 1H), 6.37 (s, 1H), 5.94 (m, 1H),5.85-5.68 (m, 1H), 5.27 (d, J=4.8 Hz, 2H), 4.89 (d, J=6.0 Hz, 2H), 4.60(q, J=7.2 Hz, 2H), 4.44 (q, J=6.9 Hz, 2H), 4.12 (t, J=6.3 Hz, 2H), 3.35(t, J=6.3 Hz, 2H), 3.16 (s, 3H), 2.19 (s, 3H), 2.05 (s, 3H), 1.86 (tt,J=6.3, 6.3 Hz, 2H), 1.26 (t, J=6.9 Hz, 3H), 1.18 (t, J=7.2 Hz, 3H).LC-MS calculated for C₄₀H₄₅N₁₂O₆ (M+H)⁺: m/z=789.4; found 789.3.

Example 29.(E)-9-(4-(5-carbamoyl-7-(3-cyanopropoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

To a vial was added(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-hydroxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 28: 1.9 mg, 2.409 μmol), DMF (0.241 ml), cesium carbonate(1.726 mg, 5.30 μmol), 4-bromobutanenitrile (Combi-Blocks, cat #QE-2324:0.239 μl, 2.409 μmol) and a stir bar. The mixture was stirred at rt for15 min, then heated at 50° C. for 10 min. After cooling to rt, themixture was diluted with MeCN, and purified by prep HPLC (pH=2,MeCN/water+TFA) to provide the desired compound as the TFA salt. LC-MScalculated for C₄₄H₅₀N₁₃O₆ (M+H)⁺: m/z=856.4; found 856.4.

Example 30.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-isopropoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 29 with 2-bromopropane (Aldrich, cat #B78114) replacing4-bromobutanenitrile. After cooling to rt, the mixture was diluted withMeCN, and purified by prep HPLC (pH=2, MeCN/water+TFA) to provide thedesired compound as the TFA salt. LC-MS calculated for C₄₃H₅₁N₁₂O₆(M+H)⁺: m/z=831.4; found 831.3.

Example 31.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(4-methylpiperazin-1-yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 27, Step 2 with 1-methylpiperazine (Aldrich, cat #130001)replacing morpholine. The reaction was diluted with MeCN, and purifiedby prep HPLC (pH=2, MeCN/water+TFA) to provide the desired compound asthe TFA salt. LC-MS calculated for C₄₈H₆₂N₁₄O₆(M+2H)²⁺: m/z=465.2; found465.5.

Example 32.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indole-6-carboxamide

Step 1:(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 15, Step 10 with2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indole-6-carboxamide(Example 23, Step 3) replacing2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide.LC-MS calculated for C₄₇H₅₂FN₁₃O₆ (M+2H)²⁺: m/z=456.7; found 457.0.

Step 2:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indole-6-carboxamide

To a solution of(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (15.3 mg, 0.017 mmol) in DMF(0.168 ml) was added 1 N aqueous sodium hydroxide (0.0336 ml, 0.034mmol). The mixture was stirred for 15 min at rt and was diluted withMeCN and water, and purified by prep HPLC (pH=2, MeCN/water+TFA) toprovide the desired product as the TFA salt. LC-MS calculated forC₄₀H₄₃FN₁₁O₅ (M+H)⁺: m/z=776.3; found 776.3.

Example 33.(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

Step 1: tert-butyl(3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl)carbamate

This compound was prepared using similar procedures as described forExample 15, Step 2 with tert-butyl (3-bromopropyl)carbamate (Aldrich,cat #17356) replacing (3-bromopropoxy)(tert-butyl)dimethylsilane. LC-MScalculated for C₁₁H₁₃ClN₃O₆(M-C₄H₇)⁺: m/z=318.0; found 318.0.

Step 2: (E)-2-(4-bromobut-2-en-1-yl)isoindoline-1,3-dione

A solution of (E)-1,4-dibromobut-2-ene (Aldrich, cat #D39207: 23.10 g,108 mmol) and potassium carbonate (16.42 g, 119 mmol) in DMF (50.0 ml)at room temperature was treated with phthalimide, potassium salt(Aldrich, cat #160385: 10 g, 54.0 mmol). The reaction mixture wasstirred at rt for 24 h, filtered, and concentrated in vacuo. Theresulting oil was diluted with ethyl acetate (200 mL), washed with PBSbuffer (2×100 mL), dried over MgSO₄, filtered and concentrated in vacuo.The crude oil was purified by column chromatography (0-20% ethylacetate/hexanes). LC-MS calculated for C₁₂H₁₁BrNO₂ (M+H)⁺:m/z=280.0/282.0; found 280.1/282.1.

Step 3:(E)-9-(4-(1,3-dioxoisoindolin-2-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

To a solution of (E)-2-(4-bromobut-2-en-1-yl)isoindoline-1,3-dione(0.034 g, 0.122 mmol) and2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 12, Step 3: 0.05 g, 0.122 mmol) in DMF (0.769 ml) was addedDIPEA (0.064 ml, 0.367 mmol) and cesium carbonate (0.120 g, 0.367 mmol).The mixture was stirred at rt overnight. After cooling with an ice bath,water was added, and the reaction was extracted with 3:1 CHCl₃/IPA. Thecombined organic extracts were dried over MgSO₄, filtered, and purifiedby silica gel chromatography (0-10% MeOH/DCM) to provide the desiredproduct as a white solid.

LC-MS calculated for C₃₃H₃₄N₇O₅ (M+H)⁺: m/z=608.3; found 608.3.

Step 4:(E)-9-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

To a solution of(E)-9-(4-(1,3-dioxoisoindolin-2-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(0.036 g, 0.059 mmol) in ethanol (0.846 ml) at room temperature wasadded hydrazine monohydrate (0.029 ml, 0.592 mmol). After 10 min ofstirring at rt, the reaction mixture was warmed to 60° C. for 2 h, thencooled to 0° C. in an ice bath. The resulting slurry was filtered, andthe filtrate was concentrated in vacuo. The resulting solid was purifiedby flash chromatography (6% NH₄OH in methanol). LC-MS calculated forC₂₅H₃₂N₇O₃ (M+H)⁺: m/z=478.2; found 478.3.

Step 5: tert-butyl(E)-(3-(5-carbamoyl-2-((4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)amino)-3-nitrophenoxy)propyl)carbamate

To a vial was added tert-butyl(3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl)carbamate (0.121 g, 0.324mmol),(E)-9-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(0.155 g, 0.324 mmol), EtOH (1.619 ml), and DIPEA (0.283 ml, 1.619mmol). The mixture was sealed, then heated at 120° C. overnight withstirring. After cooling to rt, the mixture was concentrated underreduced pressure and purified by silica gel chromatography (15%MeOH/DCM). LC-MS calculated for C₄₀H₅₁N₁₀O₉ (M+H)⁺: m/z=815.4; found815.5.

Step 6: tert-butyl(E)-(3-(3-amino-5-carbamoyl-2-((4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)amino)phenoxy)propyl)carbamate

To a vial was added a stir bar, tert-butyl(E)-(3-(5-carbamoyl-2-((4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)amino)-3-nitrophenoxy)propyl)carbamate(0.040 g, 0.049 mmol), ammonium chloride (0.018 g, 0.344 mmol), and zinc(0.022 g, 0.344 mmol). 1,4-Dioxane (0.736 ml) and water (0.245 ml) wereadded and the mixture was stirred at rt for 10 min.

The resulting mixture was filtered and extracted with CHCl₃/IPA (3:1).The combined organic extracts were dried over MgSO₄, filtered, andconcentrated in vacuo. The crude product was used directly in the nextstep without further purification. LC-MS calculated for C₄₀H₅₃N₁₀O₇(M+H)⁺: m/z=785.4; found 785.5.

Step 7: tert-butyl(E)-(3-((2-amino-5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamate

This compound was prepared using similar procedures as described forExample 1, Step 4 with tert-butyl(E)-(3-(3-amino-5-carbamoyl-2-((4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)amino)phenoxy)propyl)carbamatereplacing tert-butyl(E)-(4-((2-amino-4-carbamoyl-6-methylphenyl)amino)but-2-en-1-yl)carbamate.LC-MS calculated for C₄₁H₅₂N₁₁O₇ (M+H)⁺: m/z=810.4; found 810.4.

Step 8: tert-butyl(E)-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamate

This compound was prepared using similar procedures as described forExample 15, Step 6 with tert-butyl(E)-(3-((2-amino-5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamatereplacing tert-butyl(E)-(4-(2-amino-5-carbamoyl-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate.LC-MS calculated for C₄₈H₆₀N₁₃O₈ (M+H)⁺: m/z=946.5; found 946.6.

Step 9:(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

To a solution of tert-butyl(E)-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamate(0.050 g, 0.053 mmol) in 1,4-dioxane (0.528 ml) was added 4.0 M HCl indioxane (0.132 ml, 0.528 mmol). The mixture was stirred for 15 min, thenwas diluted with MeCN/water and purified by prep HPLC (pH=2,MeCN/water+TFA) to provide the desired compound as the TFA salt. LC-MScalculated for C₄₃H₅₂N₁₃O₆ (M+H)⁺: m/z=846.4; found 846.4.

Example 34.(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoicAcid

Step 1: methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate

In a 1 dram vial,(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(6 mg, 7.09 μmol) was dissolved in DMF (709 μl). Mono-methyl glutarate(Aldrich, cat #M47353: 2.67 μl, 0.021 mmol), DIPEA (3.72 μl, 0.021 mmol)and BOP (9.41 mg, 0.021 mmol) were added to the reaction mixturesequentially. After 15 min, the reaction mixture was concentrated todryness and used directly in the next step without further purification.LC-MS calculated for C₄₉H₆₀N₁₃O₉ (M+H)⁺: m/z=974.5; found 974.6.

Step 2:(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoicAcid

In a 1 dram vial, methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate(6.91 mg, 7.09 μmol) was dissolved in THF (0.140 ml), MeOH (0.071 ml),and 2.0 N LiOH (70.9 μl, 0.142 mmol). The mixture was stirred at rt for15 min, then the reaction was diluted in MeCN/water and purified by prepHPLC (pH=2, MeCN/water+TFA) to provide the desired compound as the TFAsalt. ¹H NMR (600 MHz, DMSO) δ 12.78 (s, 1H), 9.48 (s, 1H), 8.41 (d,J=1.2 Hz, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.79-7.64 (m, 1H), 7.61 (s,1H), 7.56 (s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 7.23 (s, 1H), 6.79 (s,1H), 6.41 (s, 1H), 5.86 (m, 1H), 5.74-5.68 (m, 1H), 5.27-5.24 (m, 2H),4.89-4.87 (m, 2H), 4.63-4.58 (m, 2H), 4.46 (m, 2H), 4.04 (t, J=6.4 Hz,2H), 3.89-3.84 (m, 2H), 3.31 (t, J=6.3 Hz, 2H), 3.15 (s, 3H), 2.97-2.93(m, 2H), 2.19 (s, 3H), 2.15 (t, J=7.4 Hz, 2H), 2.07 (s, 3H), 2.02-1.97(m, 2H), 1.78 (dt, J=12.3, 6.4 Hz, 2H), 1.63 (dt, J=14.8, 7.5 Hz, 2H),1.53-1.45 (m, 2H), 1.27 (t, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H). LC-MScalculated for C₄₈H₅₉N₁₃O₉(M+2H)²⁺: m/z=480.7; found 480.9.

Example 35.(E)-2-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

Step 1:3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chloro-5-nitrobenzamide

This compound was prepared using similar procedures as described forExample 15, Step 2 with (2-bromoethoxy)(tert-butyl)dimethylsilane(Aldrich, cat #428426) replacing(3-bromopropoxy)(tert-butyl)dimethylsilane. LC-MS calculated forC₁₅H₂₄ClN₂O₅Si (M+H)⁺: m/z=375.1; found 375.3.

Step 2: tert-butyl(E)-(4-((2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-carbamoyl-6-nitrophenyl)amino)but-2-en-1-yl)carbamate

This compound was prepared using similar procedures as described forExample 15, Step 3 with3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chloro-5-nitrobenzamidereplacing3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-chloro-5-nitrobenzamide.LC-MS calculated for C₂₄H₄₀N₄NaO₇Si (M+Na)⁺: m/z=547.3; found 547.3.

Step 3: tert-butyl(E)-(4-((2-amino-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-carbamoylphenyl)amino)but-2-en-1-yl)carbamate

This compound was prepared using similar procedures as described forExample 1, Step 3 with tert-butyl(E)-(4-((2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-carbamoyl-6-nitrophenyl)amino)but-2-en-1-yl)carbamatereplacing tert-butyl(E)-(4-((4-carbamoyl-2-methyl-6-nitrophenyl)amino)but-2-en-1-yl)carbamate.LC-MS calculated for C₂₄H₄₃N₄O₅Si (M+H)⁺: m/z=495.3; found 495.4.

Step 4: tert-butyl(E)-(4-(2-amino-5-carbamoyl-7-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate

This compound was prepared using similar procedures as described forExample 1, Step 4 with tert-butyl(E)-(4-((2-amino-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-carbamoylphenyl)amino)but-2-en-1-yl)carbamatereplacing tert-butyl(E)-(4-((2-amino-4-carbamoyl-6-methylphenyl)amino)but-2-en-1-yl)carbamate.LC-MS calculated for C₁₉H₂₈N₅O₅ (M+H)⁺: m/z=406.2; found 406.2.

Step 5:(E)-2-((1-(4-((tert-butoxycarbonyl)amino)but-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 15, Step 6 with tert-butyl(E)-(4-(2-amino-5-carbamoyl-7-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamatereplacing tert-butyl(E)-(4-(2-amino-5-carbamoyl-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate.LC-MS calculated for C₃₃H₄₄N₉O₇ (M+H)⁺: m/z=678.3; found 678.4.

Step 6:(E)-2-((1-(4-aminobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 1, Step 6 with(E)-2-((1-(4-((tert-butoxycarbonyl)amino)but-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing tert-butyl(E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate.LC-MS calculated for C₂₈H₃₆N₉O₅ (M+H)⁺: m/z=578.3; found 578.2.

Step 7:(E)-2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 1, Step 7 with(E)-2-((1-(4-aminobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing(E)-1-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide.LC-MS calculated for C₂₈H₃₅N₈O₆ (M+H)⁺: m/z=579.3; found 579.3.

Step 8:(E)-2-((1-(4-bromobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 1, Step 8 with(E)-2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing(E)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-enyl)-7-methyl-1H-benzo[d]imidazole-5-carboxamide.LC-MS calculated for C₂₈H₃₄BrNO₅ (M+H)⁺: m/z=641.2/643.2; found641.3/643.3.

Step 9:(E)-2-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

To a mixture of(E)-2-((1-(4-bromobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (120 mg, 0.187 mmol) and2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(76 mg, 0.187 mmol) in DMF (1871 μl) was added DIPEA (98 μl, 0.561mmol). After 5 min, Cs₂CO₃ (183 mg, 0.561 mmol) was added. The mixturewas stirred at rt overnight. The reaction mixture was diluted withTFA/water, then purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated forC₄₉H₅₇N₁₄O₈ (M+H)⁺: m/z=969.4; found 969.4.

Example 36.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 32, Step 2 with(E)-2-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (Example 35, Step 9)replacing(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate. ¹H NMR (600 MHz, DMSO) δ12.77 (s, 1H), 9.49 (s, 1H), 8.42 (m, 1H), 8.04 (s, 1H), 7.93 (s, 1H),7.62 (s, 1H), 7.57 (s, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 7.26 (s, 1H),6.79 (s, 1H), 6.40 (s, 1H), 5.94 (m, 1H), 5.75-5.67 (m, 1H), 5.26 (d,J=4.8 Hz, 2H), 4.90 (d, J=5.6 Hz, 2H), 4.61 (dd, J=14.1, 7.0 Hz, 2H),4.46 (d, J=6.5 Hz, 2H), 4.10-4.01 (m, 2H), 3.95-3.86 (m, 2H), 3.35 (m,2H), 3.30 (m, 2H), 3.15 (d, J=4.9 Hz, 3H), 2.19 (s, 3H), 2.07 (s, 3H),1.85-1.77 (m, 2H), 1.32-1.24 (m, 3H), 1.20 (t, J=7.1 Hz, 3H). LC-MScalculated for C₄₂H₄₉N₁₂O₇ (M+H)⁺: m/z=833.4; found 833.4.

Example 37.(6S,9S,12S,15S)-15-amino-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-6,9-bis(carboxymethyl)-12-(3-guanidinopropyl)-5,8,11,14-tetraoxo-4,7,10,13-tetraazaheptadecan-17-oicAcid

Step 1: tert-butyl(6S,9S,12S,15S)-15-amino-6,9-bis(2-(tert-butoxy)-2-oxoethyl)-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-5,8,11,14-tetraoxo-12-(3-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-4,7,10,13-tetraazaheptadecan-17-oate

In a 1 dram vial,(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 33, Step 9: 37 mg, 0.044 mmol) was dissolved in DMF (875 μl).Fmoc-Asp(OtBu)-Arg(Pbf)-Asp(OtBu)-Asp(OtBu)-OH (Peptides International,cat #PCS-33379-PI: 73.5 mg, 0.066 mmol), DIPEA (38.2 μl, 0.219 mmol) andBOP (38.7 mg, 0.087 mmol) were added to the reaction mixturesequentially. After stirring for 15 min, piperidine (0.1 mL) was added.After 30 min, the reaction mixture was diluted with MeOH then purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas the TFA salt. LC-MS calculated for C₈₆H₁₂₀N₂₀O₁₉S (M+2H)²⁺:m/z=884.4; found 884.5.

Step 2:(6S,9S,12S,15S)-15-amino-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-6,9-bis(carboxymethyl)-12-(3-guanidinopropyl)-5,8,11,14-tetraoxo-4,7,10,13-tetraazaheptadecan-17-oicAcid

Tert-butyl(6S,9S,12S,15S)-15-amino-6,9-bis(2-(tert-butoxy)-2-oxoethyl)-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-5,8,11,14-tetraoxo-12-(3-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-4,7,10,13-tetraazaheptadecan-17-oate(5 mg, 2.83 μmol) was stirred in TFA (0.5 mL) for 5 min. The reactionwas diluted with MeCN then purified by prep HPLC (pH=2, MeCN/water+TFA)to provide the desired compound as the TFA salt. ¹H NMR (600 MHz, DMSO)δ 12.78 (s, 1H), 9.48 (s, 1H), 8.59 (d, J=7.2 Hz, 1H), 8.41 (s, 1H),8.26 (d, J=7.2 Hz, 1H), 8.18-8.06 (ovrlp m, 3H), 8.05 (s, 1H), 7.93 (s,1H), 7.72 (m, 1H), 7.60 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.36 (s,1H), 7.34 (s, 1H), 7.23 (s, 1H), 6.79 (s, 1H), 6.37 (s, 1H), 5.85 (m,1H), 5.69 (m, 1H), 5.26 (s, 2H), 4.87 (s, 2H), 4.61 (m, 2H), 4.52 (dd,J=13.6, 7.4 Hz, 1H), 4.43 (ovrlp m, 4H), 4.27 (dd, J=13.6, 7.4 Hz, 1H),4.12 (s, 1H), 4.09-4.00 (m, 2H), 3.89 (m, 2H), 3.31 (dd, J=6.3, 6.3 Hz,2H), 3.15 (s, 3H), 3.10-3.00 (ovrlp m, 3H), 2.96 (m, 1H), 2.83 (dd,J=17.8, 3.3 Hz, 1H), 2.76-2.62 (ovrlp m, 2H), 2.567-2.50 (m, 3H), 2.20(s, 3H), 2.06 (s, 3H), 1.83-1.73 (m, 2H), 1.65 (m, 1H), 1.55-1.42 (m,4H), 1.33-1.24 (m, 3H), 1.21-1.16 (m, 3H). LC-MS calculated forC₆₁H₈₀N₂₀O₁₆ (M+2H)²⁺: m/z=674.3; found 674.5.

Example 38.(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

To a vial was added(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(l-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 36: 0.003 g, 3.60 μmol), DMF (0.360 ml), and a stir bar. Themixture was cooled to 0° C., and DMP (3.06 mg, 7.20 μmol) and water(0.519 μl, 0.029 mmol) were added. The mixture was warmed to rt andstirred overnight. To this mixture was then added morpholine (0.941 μl,10.81 μmol), acetic acid (3.09 μl, 0.054 mmol), then sodiumcyanoborohydride (0.453 mg, 7.20 μmol). After stirring for 15 min, thereaction was diluted with water/MeCN and purified by prep HPLC (pH=2,MeCN/water+TFA) to provide the desired compound as the TFA salt. LC-MScalculated for C₄₆H₅₇N₁₃O₇(M+2H)²⁺: m/z=451.7; found 451.7.

Example 39.(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)propanoicAcid

Step 1: tert-butyl 3-(((4-nitrophenoxy)carbonyl)oxy)propanoate

To a solution of tert-butyl 3-hydroxypropanoate (Aldrich, cat #90218:0.247 g, 1.69 mmol) and N-methylmorpholine (0.539 ml, 4.90 mmol) in dryTHF (8.5 ml) was added 4-nitrophenyl carbonochloridate (Aldrich, cat#160210: 0.681 g, 3.38 mmol) at 0° C. and the resulting mixture wasstirred at rt for 1 h. After completion of the reaction, the reactionwas cooled to 0° C. and water was added. The aqueous phase was extractedwith CH₂Cl₂. The organic extracts were dried over MgSO₄, filtered, andthe solvent was removed. The crude mixture was purified byflash-chromatography (1:8 EtOAc/hexanes) to afford the desired productas an oil. LC-MS calculated for C₁₄H₁₇NNaO₇ (M+Na)⁺: m/z=334.1; found334.0.

Step 2: tert-butyl(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)propanoate

To a solution of(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 33, Step 9: 0.015 g, 0.018 mmol) in DMF (0.177 ml) was addedDIPEA (9.29 μl, 0.053 mmol). After cooling to 0° C., tert-butyl3-(((4-nitrophenoxy)carbonyl)oxy)propanoate (5.52 mg, 0.018 mmol) wasadded and the mixture was warmed to rt and stirred for 1 h. The mixturewas cooled to 0° C. and quenched with water. The reaction was extractedwith CHCl₃/IPA (3:1) and the combined organic layers were dried overMgSO₄, filtered, and concentrated under reduced pressure. The crudeproduct was used directly in the next step without further purification.LC-MS calculated for C₅₁H₆₄N₁₃O₁₀ (M+H)⁺: m/z=1018.5; found 1018.6.

Step 3:(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)propanoicAcid

This compound was prepared using similar procedures as described forExample 37, Step 2 with tert-butyl(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)propanoatereplacing tert-butyl(6S,9S,12S,15S)-15-amino-6,9-bis(2-(tert-butoxy)-2-oxoethyl)-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-5,8,11,14-tetraoxo-12-(3-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-4,7,10,13-tetraazaheptadecan-17-oate.¹H NMR (600 MHz, DMSO) δ 12.78 (s, 1H), 9.47 (s, 1H), 8.41 (d, J=1.2 Hz,1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.56 (d, J=1.2 Hz, 1H),7.35 (s, 1H), 7.31 (s, 1H), 7.24 (d, J=0.6 Hz, 1H), 7.10 (t, J 5.7 Hz,1H), 6.79 (s, 1H), 6.40 (s, 1H), 5.85 (m, 1H), 5.72 (dt, J=15.6, 5.4 Hz,1H), 5.25 (d, J=4.8 Hz, 2H), 4.87 (d, J=5.4 Hz, 2H), 4.61 (q, J=6.9 Hz,2H), 4.45 (1, J=6.9 Hz, 2H), 4.03 (ovrlp dt, J=11.4, 6.6 Hz, 4H), 3.88(t, J=6.3 Hz, 2H), 3.31 (t, J=6.0 Hz, 2H), 3.15 (s, 3H), 2.89 (m, 2H),2.46 (t, J=6.0 Hz, 2H), 2.19 (s, 3H), 2.07 (s, 3H), 1.78 (dt, J=12.6,6.3 Hz, 2H), 1.52 (dt, J=12.6, 6.3 Hz, 2H), 1.27 (t, J=6.9 Hz, 3H), 1.20(t, J=6.9 Hz, 3H). LC-MS calculated for C₄₇H₅₇N₁₃O₁₀ (M+2H)²⁺:m/z=481.7; found 481.5.

Example 40.(E)-2-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)aceticAcid

Step 1: methyl 2-(((4-nitrophenoxy)carbonyl)oxy)acetate

This compound was prepared using similar procedures as described forExample 39, Step 1 with methyl 2-hydroxyacetate (Aldrich, cat #325260)replacing 3-hydroxypropanoate. The crude product was purified usingsilica gel chromatography (0-24% EtOAc/hexanes) to provide the desiredcompound as an oil. LC-MS calculated for C₁₀H₁₀NO₇ (M+H)⁺: m/z=256.0;found 256.1.

Step 2: methyl(E)-2-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)acetate

This compound was prepared using similar procedures as described forExample 39, Step 2 with methyl 2-(((4-nitrophenoxy)carbonyl)oxy)acetatereplacing tert-butyl 3-(((4-nitrophenoxy)carbonyl)oxy)propanoate. LC-MScalculated for C₄₇H₅₆N₁₃O₁₀ (M+H)⁺: m/z=962.4; found 962.5.

Step 3:(E)-2-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)aceticAcid

This compound was prepared using similar procedures as described forExample 34, Step 2 with methyl(E)-2-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)acetatereplacing methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate.¹H NMR (600 MHz, DMSO) δ 12.77 (s, 1H), 9.47 (s, 1H), 8.41 (d, J=1.2 Hz,1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.37-7.29(ovrlp m, 2H), 7.24 (s, 1H), 6.79 (s, 1H), 6.39 (s, 1H), 5.85 (m, 1H),5.74-5.67 (m, 1H), 5.25 (d, J=4.2 Hz, 2H), 4.87 (d, J=4.2 Hz, 2H), 4.61(q, J=7.2 Hz, 2H), 4.48-4.41 (m, 2H), 4.36 (s, 2H), 4.05 (t, J=5.7 Hz,2H), 3.90 (t, J 5.7 Hz, 2H), 3.31 (t, J=5.7 Hz, 2H), 3.15 (s, 3H), 2.92(m, 3H), 2.19 (s, 3H), 2.07 (s, 2H), 1.78 (tt, J=5.7, 5.7 Hz, 2H),1.56-1.50 (m, 2H), 1.26 (t, J=7.2 Hz, 3H), 1.19 (t, J=7.2 Hz, 3H). LC-MScalculated for C₄₆H₅₅N₁₃O₁₀ (M+2H)²⁺: m/z=474.7; found 474.8.

Example 41.(E)-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)glycine

To a vial was added(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 33, Step 9: 0.015 g, 0.018 mmol), DIPEA (9.29 μl, 0.053 mmol),then ethyl 2-isocyanatoacetate (Aldrich, cat #238627: 2.98 μl, 0.027mmol). The mixture was stirred at rt overnight, and then wasconcentrated under reduced pressure. To the resulting crude mixture wasadded THF (0.180 ml, 2.199 mmol), MeOH (0.089 ml, 2.199 mmol), andaqueous 2 M LiOH (0.089 ml, 0.177 mmol). The mixture was stirred for 15min at rt and was then diluted with water and purified by prep HPLC(pH=2, MeCN/water+TFA) to provide the desired product as the TFA salt.¹H NMR (600 MHz, DMSO) δ 12.77 (s, 1H), 9.48 (s, 1H), 8.41 (d, J=1.5 Hz,1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.61 (s, 1H), 7.57 (d, J=1.5 Hz, 1H),7.35 (s, 1H), 7.31 (s, 1H), 7.25 (s, 1H), 6.79 (s, 1H), 6.39 (s, 1H),6.13 (t, J=6.0 Hz, 1H), 5.99 (t, J 5.4 Hz, 1H), 5.86 (m, 1H), 5.73-5.67(m, 1H), 5.26 (d, J=4.8 Hz, 2H), 4.87 (d, J=4.8 Hz, 2H), 4.60 (q, J=7.2Hz, 2H), 4.45 (br q, J=6.9 Hz, 2H), 4.05 (t, J=6.6 Hz, 2H), 3.88 (t,J=6.0 Hz, 2H), 3.64 (d, J=5.4 Hz, 11H), 3.27 (t, J=6.0 Hz, 2H), 3.15 (s,3H), 2.94 (m, 2H), 2.19 (s, 3H), 2.07 (s, 3H), 1.78 (tt, J 6.6, 6.0 Hz,2H), 1.49 (tt, J=6.0, 6.0 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H), 1.19 (t,J=6.9 Hz, 3H). LC-MS calculated for C₄₆H₅₅N₁₄O₉ (M+H)⁺: m/z=947.4; found947.4.

Example 42

(S,E)-3-amino-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoicAcid

Step 1: methyl(S,E)-3-amino-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoate

In a 1 dram vial,(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 33, Step 9: 10 mg, 0.012 mmol) was dissolved in DMF (236 μl).(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-methoxy-4-oxobutanoicacid (Aurum Pharmatech, cat #B-7268: 8.73 mg, 0.024 mmol), DIPEA (10.32μl, 0.059 mmol) and BOP (10.46 mg, 0.024 mmol) were added to thereaction mixture sequentially. After 15 min, piperidine (0.1 mL) wasadded. After 1 h, the reaction mixture was diluted with MeOH thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₄₈H₆₀N₁₄O₉(M+2H)²⁺:m/z=488.2; found 488.5.

Step 2:(S,E)-3-amino-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoicAcid

This compound was prepared using similar procedures as described forExample 34, Step 2 with methyl(S,E)-3-amino-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoatereplacing methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate.LC-MS calculated for C₄₇H₅₈N₁₄O₉(M+2H)²⁺: m/z=481.2; found 481.3.

Example 43.(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoicAcid

Step 1: tert-butyl(E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate

To a solution of(E)-3-((1-(4-((tert-butoxycarbonyl)amino)but-2-en-1l-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (Example 15, Step 6: 0.406 g,0.587 mmol) in THF (1.956 ml) and MeOH (0.978 ml) was added 2 M LiOH(0.880 ml, 1.761 mmol). The reaction was stirred at rt for 15 min, thenwater and DCM were added and the layers were separated. The aqueouslayer was further extracted with DCM, and the combined organic layerswere dried over MgSO₄, filtered, and concentrated under reducedpressure. The crude product was used directly in the next step withoutfurther purification. LC-MS calculated for C₂₇H₃₈N₇O₆ (M+H)⁺: m/z=556.3;found 556.5.

Step 2: ethyl(E)-3-(((3-((1-(4-((tert-butoxycarbonyl)amino)but-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoate

To a solution of tert-butyl(E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate(0.050 g, 0.090 mmol) and DIPEA (0.024 ml, 0.135 mmol) in THF (0.900 ml)was added ethyl 3-isocyanatopropionate (Aldrich, cat #479012: 0.012 ml,0.090 mmol). The reaction was stirred at 70° C. overnight. After coolingto rt, the reaction was diluted with water and CHCl₃/IPA (3:1), and thelayers were separated. The aqueous layer was further extracted and thecombined organic extracts were dried over MgSO₄, filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography (30% MeOH/DCM). LC-MS calculated forC₃₃H₄₇N₈O₉ (M+H)⁺: m/z=699.3; found 699.7.

Step 3: ethyl(E)-3-(((3-((1-(4-aminobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoate

To a solution of ethyl(E)-3-(((3-((1-(4-((tert-butoxycarbonyl)amino)but-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoate(0.066 g, 0.094 mmol) in dioxane (0.945 ml) was added 4 M HCl in dioxane(0.236 ml, 0.945 mmol). The reaction was stirred for 1 h, then wasconcentrated under reduced pressure and used directly in the next stepwithout further purification. LC-MS calculated for C₂₈H₃₉N₈O₇ (M+H)⁺:m/z=599.3; found 599.3.

Step 4: ethyl(E)-3-(((3-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoate

This compound was prepared using similar procedures as described forExample 1, Step 7 with ethyl(E)-3-(((3-((1-(4-aminobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoatereplacing(E)-1-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide.The crude product was purified using silica gel chromatography (20%MeOH/DCM). LC-MS calculated for C₂₈H₃₈N₇O₈ (M+H)⁺: m/z=600.3; found600.3.

Step 5: ethyl(E)-3-(((3-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-((methylsulfonyl)oxy)but-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoate

To a vial was added ethyl(E)-3-(((3-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoate(0.028 g, 0.047 mmol), THF (0.467 ml), Et₃N (9.76 μl, 0.070 mmol), thenMs-Cl (4.37 μl, 0.056 mmol). After stirring at rt for 1 h, the reactionwas quenched with aqueous saturated sodium bicarbonate, and extractedwith CHCl₃/IPA (3:1). The combined organic layers were dried over MgSO₄,filtered, and concentrated under reduced pressure. The crude product wasused directly in the next step without further purification. LC-MScalculated for C₂₉H₄₀N₇O₁₀S (M+H)⁺: m/z=678.3; found 678.3.

Step 6: ethyl(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoate

To a solution of ethyl(E)-3-(((3-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-((methylsulfonyl)oxy)but-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoate(0.030 g, 0.044 mmol) in DMF (0.443 ml) was added2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 12, Step 3: 0.018 g, 0.044 mmol) and cesium carbonate (0.043 g,0.133 mmol). The mixture was stirred for 3 h at rt, and was then dilutedwith water. The mixture was extracted with CHCl₃/IPA (3:1) and thecombined organic extracts were dried over MgSO₄, filtered, andconcentrated under reduced pressure. The crude product was used directlyin the next step without further purification. LC-MS calculated forC₄₉H₆₀N₁₃O₁₀ (M+H)⁺: m/z=990.4; found 990.0.

Step 7:(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoicAcid

To a solution of ethyl(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoatewas added THF (0.440 mL), MeOH (0.221 mL) and aqueous 2 M LiOH (0.221ml, 0.443 mmol). After stirring 15 min at rt, the mixture was dilutedwith water, and purified by prep HPLC (pH=2, MeCN/water+TFA) to providethe desired compound as the TFA salt. LC-MS calculated for C₄₇H₅₆N₁₃O₁₀(M+H)⁺: m/z=962.4; found 962.4.

Example 44.(E)-3-(2-(2-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoicAcid

Step 1: tert-butyl3-(2-(2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethoxy)ethoxy)propanoate

To a suspension of 4-chloro-3-hydroxy-5-nitrobenzamide (0.200 g, 0.923mmol), and cesium carbonate (0.451 g, 1.385 mmol) in DMF (2.309 ml) wasadded tert-butyl 3-(2-(2-bromoethoxy)ethoxy)propanoate (Combi-Blocks,cat #QD-1308: 0.329 g, 1.108 mmol). After stirring at 50° C. for 4 h,the reaction was diluted with water and DCM, and the layers wereseparated. The aqueous layer was further extracted with DCM, and thecombined organic layers were dried over MgSO₄, filtered, andconcentrated under reduced pressure. The resulting crude oil waspurified by silica gel chromatography (5% MeOH/DCM). LC-MS calculatedfor C₁₈H₂₅ClN₂NaO₈ (M+Na)⁺: m/z=455.1; found 455.1.

Step 2: (E)-2-(4-hydroxybut-2-en-1-yl)isoindoline-1,3-dione

To a solution of (E)-but-2-ene-1,4-diol (Astatech, cat #70835: 1.198 g,13.59 mmol) in tetrahydrofuran (34.0 ml) was added triphenylphosphine(3.57 g, 13.59 mmol). After cooling to 0° C., isoindoline-1,3-dione (1.0g, 6.80 mmol) was added. A 40% wt/v solution of DEAD (5.92 ml, 13.59mmol) in toluene was added dropwise and the reaction was warmed up to rtwith stirring for 1 h. The reaction was concentrated and purified bysilica gel column to provide the desired product (0->5% MeOH/DCM). LC-MScalculated for C₁₂H₁₂NO₃ (M+H)⁺: m/z=218.1; found 218.1.

Step 3:(E)-2-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)isoindoline-1,3-dione

To a mixture of (E)-2-(4-hydroxybut-2-en-1-yl)isoindoline-1,3-dione (1.5g, 6.91 mmol) and Et₃N (1.444 ml, 10.36 mmol) in DCM (69.1 ml) was addedTBS-Cl (1.249 g, 8.29 mmol). The mixture was stirred at rt for 16 h andwas then concentrated under reduced pressure. Saturated aqueous NaHCO₃was added to the reaction mixture followed by extraction withdichloromethane (3 times). The combined organic layers were dried overNa₂SO₄, filtered and concentrated. The crude product was added to asilica gel column and was eluted with ethyl acetate/hexane from 0% to40% to give(E)-2-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)isoindoline-1,3-dione(2.03 g, 6.12 mmol, 89% yield) as a colorless oil. LC-MS calculated forC₁₈H₂₇NO₄Si (M+NH₄)⁺: m/z=349.2; found 349.3.

Step 4: (E)-4-((tert-butyldimethylsilyl)oxy)but-2-en-1-amine

To a solution of(E)-2-(4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)isoindoline-1,3-dione(2.02 g, 6.09 mmol) in DCM (30.5 ml) and MeOH (30.5 ml) was addedhydrazine monohydrate (4.43 ml, 91 mmol). After heating for 2 h at 40°C., the mixture was filtered to remove the precipitated phthalhydrazide.The filtrate was washed with aqueous saturated NaHCO₃ and dried overMgSO₄, filtered and concentrated under reduced pressure. The crudeproduct was used without further purification. LC-MS calculated forC₁₀H₂₄NOSi (M+H)⁺: m/z=202.2; found 202.2.

Step 5: tert-butyl(E)-3-(2-(2-(2-((4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)amino)-5-carbamoyl-3-nitrophenoxy)ethoxy)ethoxy)propanoate

To a solution of tert-butyl3-(2-(2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethoxy)ethoxy)propanoate(0.400 g, 0.924 mmol) in ethanol (4.62 ml) was added DIPEA (0.807 ml,4.62 mmol) and (E)-4-((tert-butyldimethylsilyl)oxy)but-2-en-1-amine(0.186 g, 0.924 mmol). The resulting mixture was heated at 120° C.overnight. After cooling, the reaction was concentrated, and purified bysilica gel column (10% MeOH/DCM). LC-MS calculated for C₂₈H₄₈N₃O₉Si(M+H)⁺: m/z=598.3; found 598.3.

Step 6: tert-butyl(E)-3-(2-(2-(3-amino-2-((4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)amino)-5-carbamoylphenoxy)ethoxy)ethoxy)propanoate

To a solution of tert-butyl(E)-3-(2-(2-(2-((4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)amino)-5-carbamoyl-3-nitrophenoxy)ethoxy)ethoxy)propanoate(0.480 g, 0.803 mmol) in MeOH (12.04 ml) was added sodium hydrosulfite(0.699 g, 4.01 mmol) in water (2.53 ml, 141 mmol) and 30% aq. ammoniumhydroxide (1.303 ml, 10.04 mmol) at 0° C. The reaction mixture waswarmed to room temperature. After 10 min, H₂O was added to the reactionmixture followed by extraction with DCM. The combined organic layerswere dried over MgSO₄, filtered and concentrated under reduced pressure.The crude product was used directly in the next step without furtherpurification. LC-MS calculated for C₂₈H₅₀N₃O₇Si (M+H)⁺: m/z=568.3; found568.4.

Step 7: tert-butyl(E)-3-(2-(2-((2-amino-5-carbamoyl-1-(4-hydroxybut-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoate

To a solution of tert-butyl(E)-3-(2-(2-(3-amino-2-((4-((tert-butyldimethylsilyl)oxy)but-2-en-1-yl)amino)-5-carbamoylphenoxy)ethoxy)ethoxy)propanoate(0.312 g, 0.549 mmol) in MeOH (2.75 ml) was added cyanogen bromide(0.144 ml, 2.75 mmol). The mixture was stirred for 2 d, and was thenconcentrated under reduced pressure. The resulting oil was used directlyin the next step without further purification. LC-MS calculated forC₂₃H₃₅N₄O₇ (M+H)⁺: m/z=479.2; found 479.4.

Step 8:(E)-4-(7-(2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)ethoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

To a solution of tert-butyl(E)-3-(2-(2-((2-amino-5-carbamoyl-1-(4-hydroxybut-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoate(0.263 g, 0.549) in DMF (5 mL) was added DIPEA (0.768 ml, 4.40 mmol),1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (Combi-Blocks, cat#QB-0979: 0.254 g, 1.648 mmol) andbenzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate(0.729 g, 1.648 mmol). After 1 h, H₂O was added to the reaction mixturefollowed by extraction with ethyl acetate (5 mL×3). The combined organiclayers were dried over MgSO₄, filtered and concentrated under reducedpressure. The crude product was added to a silica gel column and waseluted with methanol/dichloromethane from 0% to 10% to give(E)-4-(7-(2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)ethoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate as a brown foam. LC-MScalculated for C₃₇H₅₁N₈O₉ (M+H)⁺: m/z=751.4; found 751.3.

Step 9: tert-butyl(E)-3-(2-(2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoate

To a solution of(E)-4-(7-(2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)ethoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (0.413 g, 0.550 mmol) in THF(1.833 ml) and MeOH (0.917 ml) was added 2 N LiOH (1.375 ml, 2.75 mmol).After stirring for 2 h at rt, the reaction was extracted with CHCl₃/IPA(3:1). The combined organic extracts were dried over MgSO₄, filtered,and concentrated under reduced pressure. The resulting oil was purifiedby silica gel chromatography (15% MeOH/DCM) to provide the desiredproduct as a beige foam. LC-MS calculated for C₃₀H₄₃N₆O₈ (M+H)⁺:m/z=615.3; found 615.3.

Step 10: tert-butyl(E)-3-(2-(2-((1-(4-bromobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoate

To a solution of tert-butyl(E)-3-(2-(2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-en-1-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoate(0.153 g, 0.249 mmol) in THF (1.833 ml) was added PBr₃ (0.052 ml, 0.550mmol) at 0° C. The reaction was warmed to rt and stirred for 15 min.After cooling to 0° C. the reaction was quenched with aqueous saturatedsodium bicarbonate. The reaction was extracted with DCM, and thecombined organic extracts were dried over MgSO₄, filtered, andconcentrated. The resulting brown oil was then used directly in the nextstep. LC-MS calculated for C₃₀H₄₂BrN₆O₇ (M+H)⁺: m/z=677.2/679.2; found677.2/679.2.

Step 11: tert-butyl(E)-3-(2-(2-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoate

To a solution of tert-butyl(E)-3-(2-(2-((1-(4-bromobut-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoate(0.020 g, 0.030 mmol) and2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 12, Step 3: 0.012 g, 0.030 mmol) in DMF (0.295 mL) was addedCs₂CO₃ (0.029 g, 0.089 mmol). The mixture was stirred at rt for 30 min.The mixture was diluted with water and EtOAc. The layers were separated,and the organic layer was washed with 10% brine (2×), brine, then driedover MgSO₄. The combined organic layers were filtered and concentratedunder reduced pressure. The resulting crude oil was used directly in thenext step without further purification. LC-MS calculated forC₅₁H₆₆N₁₂O₁₀ (M+2H)²⁺: m/z=503.2; found 503.5.

Step 12:(E)-3-(2-(2-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoicAcid

To a vial was added tert-butyl(E)-3-(2-(2-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoate(0.030 mg, 0.030 mmol) and TFA (0.2 mL, 2.60 mmol). The mixture wasstirred for 15 min, and was then diluted with MeCN and water andpurified by prep HPLC (pH=2, MeCN/water+TFA) to provide the desiredproduct as the TFA salt. LC-MS calculated for C₄₇H₅₇N₁₂O₁₀ (M+H)⁺:m/z=949.4; found 949.4.

Example 45.(E)-4-(N-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)sulfamoyl)butanoicAcid

Step 1: methyl(E)-4-(N-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)sulfamoyl)butanoate

To a solution of(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 33, Step 9: 0.020 g, 0.024 mmol) in THF (0.236 ml)/DMF (0.236ml) was added Et₃N (9.89 μl, 0.071 mmol) then methyl4-(chlorosulfonyl)butanoate (Enamine, cat #EN300-31554: 4.74 mg, 0.024mmol) dropwise. After stirring for 1 h at rt, the reaction was quenchedwith aqueous saturated sodium bicarbonate, and was extracted with 3:1CHCl₃/IPA. The combined organic layers were dried over MgSO₄, filtered,and concentrated under reduced pressure, and the crude product was useddirectly in the next step without further purification. LC-MS calculatedfor C₄₈H₆₀N₁₃O₁₀S (M+H)⁺: m/z=1010.4; found 1010.2.

Step 2:(E)-4-(N-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)sulfamoyl)butanoic Acid

To a solution of methyl(E)-4-(N-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)sulfamoyl)butanoate(0.024 g, 0.024 mmol) in THF (0.572 mL) and MeOH (0.236) was addedaqueous 2 N LiOH (0.236 ml, 0.473 mmol). After stirring for 15 min, themixture was diluted with water and MeCN and was purified by prep HPLC(pH=2, MeCN/water+TFA) to provide the desired compound as the TFA salt.LC-MS calculated for C₄₇H₅₈N₁₃O₁₀S (M+H)⁺: m/z=996.4; found 996.2.

Example 46.(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoicAcid

Step 1: tert-butyl 3-(3-bromo-5-carbamoyl-2-nitrophenoxy)propylcarbamate

This compound was prepared using similar procedures as described forExample 11, Step 1 with tert-butyl 3-hydroxypropylcarbamate (Aldrich,cat #416444) replacing 3-morpholinopropan-1-ol. LC-MS calculated forC₁₅H₂₁BrN₃O₆ (M+H)⁺: m/z=418.1, 420.1; found 318.1, 320.1.

Step 2: tert-butyl(3-(5-carbamoyl-3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-2-nitrophenoxy)propyl)carbamate

This compound was prepared using similar procedures as described forExample 10, Step 3 with tert-butyl3-(3-bromo-5-carbamoyl-2-nitrophenoxy)propylcarbamate replacing3-bromo-5-methoxy-4-nitrobenzamide. LC-MS calculated for C₂₅H₃₂N₇O₆(M+H)⁺: m/z=526.2; found 526.2.

Step 3: tert-butyl3-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamate

This compound was prepared using similar procedures as described forExample 10, Step 4 with tert-butyl(3-(5-carbamoyl-3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-2-nitrophenoxy)propyl)carbamatereplacing3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide.LC-MS calculated for C₂₅H₃₂N₇O₄ (M+H)⁺: m/z=494.2; found 494.3.

Step 4: (E)-tert-butyl3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamate

This compound was prepared using similar procedures as described forExample 4, Step 4 with tert-butyl3-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamatereplacing2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide.The mixture was diluted with DCM, and was washed with water and brine.The organic phase was dried over MgSO₄ before filtering. The filtratewas concentrated and purified by flash chromatography on a silica gelcolumn eluting with 0 to 20% MeOH in DCM to afford the desired product.LC-MS calculated for C₄₅H₅₄N₁₃O₇ (M+H)⁺: m/z=888.4; found 888.4.

Step 5:(E)-8-(3-aminopropoxy)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 33, Step 9 with (E)-tert-butyl3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamatereplacing tert-butyl(E)-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamate.The reaction mixture was concentrated and used in the next step withoutfurther purification. LC-MS calculated for C₄₀H₄₆N₁₃O₅ (M+H)⁺:m/z=788.4; found 788.4.

Step 6: (E)-methyl5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoate

This compound was prepared using similar procedures as described forExample 34, Step 1 with(E)-8-(3-aminopropoxy)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamidereplacing(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide.LC-MS calculated for C₄₆H₅₄N₁₃O₈ (M+H)⁺: m/z=916.4; found 916.4.

Step 7:(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoicAcid

This compound was prepared using similar procedures as described forExample 34, Step 2 with (E)-methyl5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoatereplacing methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate.The reaction mixture was diluted with MeOH and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as its TFAsalt. LC-MS calculated for C₄₅H₅₂N₁₃O₈ (M+H)⁺: m/z=902.4; found 902.4.

Example 47.(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoicAcid

Step 1: (E)-tert-butyl3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoate

This compound was prepared using similar procedures as described forExample 39, Step 2 with(E)-8-(3-aminopropoxy)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 46, Step 5) replacing(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide.LC-MS calculated for C₄₈H₅₈N₁₃O₉ (M+H)⁺: m/z=960.4; found 960.5.

Step 2:(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoicAcid

This compound was prepared using similar procedures as described forExample 37, Step 2 with (E)-tert-butyl3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1i-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoatereplacing tert-butyl(6S,9S,12S,15S)-15-amino-6,9-bis(2-(tert-butoxy)-2-oxoethyl)-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-5,8,11,14-tetraoxo-12-(3-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-4,7,10,13-tetraazaheptadecan-17-oate.The reaction mixture was diluted with MeOH and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as its TFAsalt. LC-MS calculated for C₄₄H₅₀N₁₃O₉ (M+H)⁺: m/z=904.4; found 904.5.

Example 48.(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoicAcid

Step 1:(E)-3-(1-(4-(8-(3-(tert-butoxycarbonylamino)propoxy)-6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 15, Step 10 with tert-butyl3-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamate(Example 46, Step 3) replacing2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide.LC-MS calculated for C₅₄H₆₆N₁₅O₉ (M+H)⁺: m/z=1068.5; found 1068.8.

Step 2:(E)-3-(1-(4-(8-(3-aminopropoxy)-6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 33, Step 9 with(E)-3-(1-(4-(8-(3-(tert-butoxycarbonylamino)propoxy)-6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing tert-butyl(E)-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamate.The reaction mixture was concentrated and used in the next step withoutfurther purification. LC-MS calculated for C₄₉H₅₈N₁₅O₇ (M+H)⁺:m/z=968.5; found 968.6.

Step 3:(E)-3-(5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-(5-methoxy-5-oxopentanamido)propoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 34, Step 1 with(E)-3-(1-(4-(8-(3-aminopropoxy)-6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide.LC-MS calculated for C₅₅H₆₆N₁₅O₁₀ (M+H)⁺: m/z=1096.5; found 1096.8.

Step 4:(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoicAcid

This compound was prepared using similar procedures as described forExample 34, Step 2 with(E)-3-(5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-(5-methoxy-5-oxopentanamido)propoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate.The reaction mixture was diluted with MeOH and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as its TFAsalt. LC-MS calculated for C₄₇H₅₆N₁₃O₉ (M+H)⁺: m/z=946.4; found 946.6.

Example 49.(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoicAcid

Step 1:(E)-3-(1-(4-(8-(3-((3-tert-butoxy-3-oxopropoxy)carbonylamino)propoxy)-6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 39, Step 2 with(E)-3-(1-(4-(8-(3-aminopropoxy)-6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (Example 48, Step 2)replacing(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide.LC-MS calculated for C₅₇H₇₀N₁₅O₁₁ (M+H)⁺: m/z=1140.5; found 1140.6.

Step 2:(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-7-(3-(1-ethyl-3-methyl-1H-pyrazole-5-carbonyloxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoicAcid

This compound was prepared using similar procedures as described forExample 37, Step 2 with(E)-3-(1-(4-(8-(3-((3-tert-butoxy-3-oxopropoxy)carbonylamino)propoxy)-6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing tert-butyl(6S,9S,12S,15S)-15-amino-6,9-bis(2-(tert-butoxy)-2-oxoethyl)-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-5,8,11,14-tetraoxo-12-(3-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-4,7,10,13-tetraazaheptadecan-17-oate.The reaction mixture was concentrated and used in the next step withoutfurther purification. LC-MS calculated for C₅₃H₆₂N₁₅O₁₁ (M+H)⁺:m/z=1084.5; found 1084.7.

Step 3:(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoicAcid

This compound was prepared using similar procedures as described forExample 34, Step 2 with(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-7-(3-(1-ethyl-3-methyl-1H-pyrazole-5-carbonyloxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoicacid replacing methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate.The reaction mixture was diluted with MeOH and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as its TFAsalt. LC-MS calculated for C₄₆H₅₄N₁₃O₁₀ (M+H)⁺: m/z=948.4; found 948.5.

Example 50.(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoicAcid

Step 1: 4-chloro-3-(3-methoxypropoxy)-5-nitrobenzamide

This compound was prepared using similar procedures as described forExample 15, Step 2 with 3-methoxypropan-1-ol (Aldrich, cat #38457)replacing (3-bromopropoxy)(tert-butyl)dimethylsilane. LC-MS calculatedfor C₁₁H₁₄ClN₂O₅ (M+H)⁺: m/z=289.1; found 289.0.

Step 2: (E)-tert-butyl4-(4-carbamoyl-2-(3-methoxypropoxy)-6-nitrophenylamino)but-2-enylcarbamate

This compound was prepared using similar procedures as described forExample 15, Step 3 with 4-chloro-3-(3-methoxypropoxy)-5-nitrobenzamidereplacing 3-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-chloro-5-nitrobenzamide. LC-MS calculated forC₂₀H₃₀N₄NaO₇ (M+Na)⁺: m/z=461.2; found 461.2.

Step 3: (E)-tert-butyl4-(2-amino-4-carbamoyl-6-(3-methoxypropoxy)phenylamino)but-2-enylcarbamate

This compound was prepared using similar procedures as described forExample 1, Step 3 with tert-butyl (E)-tert-butyl4-(4-carbamoyl-2-(3-methoxypropoxy)-6-nitrophenylamino)but-2-enylcarbamatereplacing tert-butyl(E)-(4-((4-carbamoyl-2-methyl-6-nitrophenyl)amino)but-2-en-1-yl)carbamate.LC-MS calculated for C₂₀H₃₃N₄O₅ (M+H)⁺: m/z=409.2; found 409.2.

Step 4: (E)-tert-butyl4-(2-amino-5-carbamoyl-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enylcarbamate

This compound was prepared using similar procedures as described forExample 1, Step 4 with (E)-tert-butyl4-(2-amino-4-carbamoyl-6-(3-methoxypropoxy)phenylamino)but-2-enylcarbamatereplacing tert-butyl(E)-(4-((2-amino-4-carbamoyl-6-methylphenyl)amino)but-2-en-1-yl)carbamate.LC-MS calculated for C₂₁H₃₂N₅O₅ (M+H)⁺: m/z=434.2; found 434.5.

Step 5: (E)-tert-butyl4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enylcarbamate

This compound was prepared using similar procedures as described forExample 1, Step 5 with (E)-tert-butyl4-(2-amino-5-carbamoyl-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enylcarbamatereplacing (E)-tert-butyl4-(2-amino-5-carbamoyl-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enylcarbamate.LC-MS calculated for C₂₈H₄₀N₇O₆ (M+H)⁺: m/z=570.3; found 570.4.

Step 6:(E)-1-(4-aminobut-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazole-5-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 6 with (E)-tert-butyl4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enylcarbamate replacing tert-butyl(E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate.LC-MS calculated for C₂₃H₃₂N₇O₄ (M+H)⁺: m/z=470.2; found 470.3.

Step 7:(E)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-enyl)-7-(3-methoxypropoxy)-1H-benzo[d]imidazole-5-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 7 with(E)-1-(4-aminobut-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazole-5-carboxamidereplacing(E)-1-(4-aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide.LC-MS calculated for C₂₃H₃₁N₆O₅ (M+H)⁺: m/z=471.2; found 471.3.

Step 8:(E)-1-(4-bromobut-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazole-5-carboxamide

This compound was prepared using similar procedures as described forExample 1, Step 8 with(E)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-enyl)-7-(3-methoxypropoxy)-1H-benzo[d]imidazole-5-carboxamidereplacing(E)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-hydroxybut-2-enyl)-7-methyl-1H-benzo[d]imidazole-5-carboxamide.LC-MS calculated for C₂₃H₃₀BrN₆O₄ (M+H)⁺: m/z=533.1/535.1; found533.1/535.1.

Step 9: (E)-tert-butyl3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamate

To a mixture of tert-butyl(3-((6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yl)oxy)propyl)carbamate(Example 46, Step 3, 35.0 mg, 0.071 mmol), and(E)-1-(4-bromobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazole-5-carboxamide(37.8 mg, 0.071 mmol) in DMF (0.4 mL) was added Cs₂CO₃ (50.8 mg, 0.156mmol). The mixture was stirred at 50° C. for 1 hour. The reactionmixture was concentrated and purified by flash chromatography on asilica gel column eluting with 0 to 20% MeOH in DCM to afford thedesired product. LC-MS calculated for C₄₈H₆₀N₁₃O₈ (M+H)⁺: m/z=946.5;found 946.5.

Step 10:(E)-8-(3-aminopropoxy)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 33, Step 9 with (E)-tert-butyl3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamatereplacing tert-butyl(E)-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamate.The reaction mixture was concentrated and used in the next step withoutfurther purification. LC-MS calculated for C₄₃H₅₂N₁₃O₆ (M+H)⁺:m/z=846.4; found 846.5.

Step 11: (E)-methyl5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoate

This compound was prepared using similar procedures as described forExample 34, Step 1 with(E)-8-(3-aminopropoxy)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamidereplacing(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide.LC-MS calculated for C₄₉H₆₀N₁₃O₉ (M+H)⁺: m/z=974.5; found 974.8.

Step 12:(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoicAcid

This compound was prepared using similar procedures as described forExample 34, Step 2 with (E)-methyl5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoate replacing methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate.The reaction mixture was diluted with MeOH and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as its TFAsalt. LC-MS calculated for C₄₈H₅₈N₁₃O₉ (M+H)⁺: m/z=960.4; found 960.5.

Example 51.(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoicAcid

Step 1: (E)-tert-butyl3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoate

This compound was prepared using similar procedures as described forExample 39, Step 2 with(E)-8-(3-aminopropoxy)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 50, Step 10) replacing(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide.LC-MS calculated for C₅₁H₆₄N₁₃O₁₀ (M+H)⁺: m/z=1018.5; found 1018.4.

Step 2:(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoicAcid

This compound was prepared using similar procedures as described forExample 37, Step 2 with (E)-tert-butyl3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1i-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoatereplacing tert-butyl(6S,9S,12S,15S)-15-amino-6,9-bis(2-(tert-butoxy)-2-oxoethyl)-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-5,8,11,14-tetraoxo-12-(3-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-4,7,10,13-tetraazaheptadecan-17-oate.The reaction mixture was diluted with MeOH and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as its TFAsalt. LC-MS calculated for C₄₇H₅₆N₁₃O₁₀ (M+H)⁺: m/z=962.4; found 962.4.

Example 52.(E)-3-((3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propoxy)carbonylamino)propanoicAcid

Step 1:(E)-8-(3-(tert-butyldimethylsilyloxy)propoxy)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 50, Step 9 with 8-(3-(tert-butyldimethylsilyloxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 13, Step 3) replacing tert-butyl(3-((6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yl)oxy)propyl)carbamate.LC-MS calculated for C₄₉H₆₅N₁₂O₇Si (M+H)⁺: m/z=961.5; found 961.6.

Step 2:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-hydroxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 33, Step 9 with(E)-8-(3-(tert-butyldimethylsilyloxy)propoxy)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamidereplacing tert-butyl(E)-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamate.The reaction mixture was concentrated and used in the next step withoutfurther purification. LC-MS calculated for C₄₃H₅₁N₁₂O₇ (M+H)⁺:m/z=847.4; found 847.4.

Step 3: (E)-ethyl3-((3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propoxy)carbonylamino)propanoate

This compound was prepared using similar procedures as described forExample 43, Step 2 with(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-hydroxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamidereplacing tert-butyl(E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate.The reaction mixture was concentrated and used in the next step withoutfurther purification. LC-MS calculated for C₄₉H₆₀N₁₃O₁₀ (M+H)⁺:m/z=990.5; found 990.7.

Step 4:(E)-3-((3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propoxy)carbonylamino)propanoicAcid

This compound was prepared using similar procedures as described forExample 34, Step 2 with (E)-ethyl3-((3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propoxy)carbonylamino)propanoatereplacing methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate.The reaction mixture was diluted with MeOH and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as its TFAsalt. LC-MS calculated for C₄₇H₅₆N₁₃O₁₀ (M+H)⁺: m/z=962.4; found 962.6.

Example 53.(E)-3-(2-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethoxy)ethoxy)propanoicAcid

Step 1: tert-butyl3-(2-(2-(3-bromo-5-carbamoyl-2-nitrophenoxy)ethoxy)ethoxy)propanoate

This compound was prepared using similar procedures as described forExample 11, Step 1 with tert-butyl3-(2-(2-hydroxyethoxy)ethoxy)propanoate (Aldrich, cat #ANV00316)replacing 3-morpholinopropan-1-ol. LC-MS calculated for C₁₈H₂₅BrN₂NaO₈(M+H)⁺: m/z=499.1, 501.1; found 499.2, 501.2.

Step 2: tert-butyl3-(2-(2-(5-carbamoyl-3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-2-nitrophenoxy)ethoxy)ethoxy)propanoate

This compound was prepared using similar procedures as described forExample 10, Step 3 with tert-butyl3-(2-(2-(3-bromo-5-carbamoyl-2-nitrophenoxy)ethoxy)ethoxy)propanoatereplacing 3-bromo-5-methoxy-4-nitrobenzamide. LC-MS calculated forC₂₈H₃₇N₆O₈ (M+H)⁺: m/z=585.3; found 585.2.

Step 3: tert-butyl3-(2-(2-((6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yl)oxy)ethoxy)ethoxy)propanoate

This compound was prepared using similar procedures as described forExample 10, Step 4 with tert-butyl3-(2-(2-(5-carbamoyl-3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-2-nitrophenoxy)ethoxy)ethoxy)propanoatereplacing3-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)pyrimidin-5-yl)-5-methoxy-4-nitrobenzamide.LC-MS calculated for C₂₈H₃₇N₆O₆ (M+H)⁺: m/z=553.3; found 553.3.

Step 4: (E)-tert-butyl3-(2-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethoxy)ethoxy)propanoate

This compound was prepared using similar procedures as described forExample 50, Step 9 with tert-butyl3-(2-(2-((6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yl)oxy)ethoxy)ethoxy)propanoatereplacing tert-butyl(3-((6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yl)oxy)propyl)carbamate.LC-MS calculated for C₅₁H₆₅N₁₂O₁₀ (M+H)⁺: m/z=1005.5; found 1005.7.

Step 5:(E)-3-(2-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethoxy)ethoxy)propanoicAcid

This compound was prepared using similar procedures as described forExample 37, Step 2 with (E)-tert-butyl3-(2-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethoxy)ethoxy)propanoatereplacing tert-butyl(6S,9S,12S,15S)-15-amino-6,9-bis(2-(tert-butoxy)-2-oxoethyl)-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-5,8,11,14-tetraoxo-2-(3-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-4,7,10,13-tetraazaheptadecan-17-oate.The reaction mixture was diluted with MeOH and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as its TFAsalt. LC-MS calculated for C₄₇H₅₇N₁₂O₁₀ (M+H)⁺: m/z=949.4; found 949.6.

Example 54.(E)-3-(2-(2-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethoxy)ethoxy)ethoxy)propanoicAcid

This compound was prepared using similar procedures as described forExample 53, with tert-butyl3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propanoate (AURUM pharmatech, cat#U37808) replacing tert-butyl 3-(2-(2-hydroxyethoxy)ethoxy)propanoate inStep 1. After finishing the final step, the reaction mixture was dilutedwith MeOH and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as its TFA salt. LC-MS calculated forC₄₉H₆₁N₁₂O₁₁ (M+H)⁺: m/z=993.5; found 993.6.

Example 55.(E)-4-(4-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethyl)piperidin-1-yl)butanoicAcid

Step 1:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(2-(piperidin-4-yl)ethoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide

This compound was prepared using similar procedures as described forExample 46, Steps 1 to 5 with tert-butyl4-(2-hydroxyethyl)piperidine-1-carboxylate (Matrix Scientific, cat#069039) replacing tert-butyl 3-hydroxypropylcarbamate in Step 1. LC-MScalculated for C₄₄H₅₂N₁₃O₅ (M+H)⁺: m/z=842.4; found 842.6.

Step 2:(E)-4-(4-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethyl)piperidin-1-yl)butanoic Acid

This compound was prepared using similar procedures as described forExample 46, Steps 6 and 7 with(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(2-(piperidin-4-yl)ethoxy)-9H-pyrimido[4,5-b]indole-6-carboxamidereplacing(E)-8-(3-aminopropoxy)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamidein Step 6. After finishing the final step, the reaction mixture wasdiluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₄₈H₅₈N₁₃O₇ (M+H)⁺: m/z=928.5; found 928.5.

Example 56.(E)-2-(4-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethyl)piperidine-1-carbonyloxy)aceticAcid

This compound was prepared using similar procedures as described forExample 40, Steps 2 and 3, with(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(2-(piperidin-4-yl)ethoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide(Example 55, Step 1) replacing(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamidein Step 2. After finishing the final step, the reaction mixture wasdiluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as its TFA salt.LC-MS calculated for C₄₇H₅₄N₁₃O₉ (M+H)⁺: m/z=944.4; found 944.5.

Example 57.(E)-3-((3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propoxy)carbonylamino)propanoicAcid

Step 1:(E)-3-(5-carbamoyl-1-(4-(6-carbamoyl-8-(3-(3-ethoxy-3-oxopropylcarbamoyloxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 52, Steps 1 to 3 with(E)-3-(1-(4-bromobut-2-enyl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (Example 15, Step 9)replacing(E)-1-(4-bromobut-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazole-5-carboxamidein Step 1.

Step 2:(E)-3-((3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propoxy)carbonylamino)propanoicAcid

This compound was prepared using similar procedures as described forExample 34, Step 2 with(E)-3-(5-carbamoyl-1-(4-(6-carbamoyl-8-(3-(3-ethoxy-3-oxopropylcarbamoyloxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate.The reaction mixture was diluted with MeOH and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as its TFAsalt. LC-MS calculated for C₄₆H₅₄N₁₃O₁₀ (M+H)⁺: m/z=948.4; found 948.5.

Example 58.(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-8-(2-(2-(2-carboxyethoxy)ethoxy)ethoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoicAcid

Step 1:(E)-3-((1-(4-(8-(2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)ethoxy)-6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate

This compound was prepared using similar procedures as described forExample 53, Steps 1 to 3 with(E)-3-(1-(4-bromobut-2-enyl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yloxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (Example 15, Step 9)replacing(E)-1-(4-bromobut-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazole-5-carboxamidein Step 1. LC-MS calculated for C₅₇H₇₁N₁₄O₁₁ (M+H)⁺: m/z=1127.5; found1127.2.

Step 2: tert-butyl(E)-3-(2-(2-((6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yl)oxy)ethoxy)ethoxy)propanoate

This compound was prepared using similar procedures as described forExample 34, Step 2 with(E)-3-((1-(4-(8-(2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)ethoxy)-6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate replacing methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate.LC-MS calculated for C₅₀H₆₃N₁₂O₁₀ (M+H)⁺: m/z=991.5; found 991.4.

Step 3: tert-butyl(E)-3-(2-(2-((6-carbamoyl-9-(4-(5-carbamoyl-7-(3-(((3-ethoxy-3-oxopropyl)carbamoyl)oxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yl)oxy)ethoxy)ethoxy)propanoate

This compound was prepared using similar procedures as described forExample 43, Step 2 with tert-butyl(E)-3-(2-(2-((6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(i-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yl)oxy)ethoxy)ethoxy)propanoatereplacing tert-butyl(E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)carbamate.The reaction mixture was concentrated and used in the next step withoutfurther purification. LC-MS calculated for C₅₆H₇₂N₁₃O₁₃ (M+H)⁺:m/z=1134.5; found 1134.6.

Step 4:(E)-3-(((3-((1-(4-(8-(2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)ethoxy)-6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoicAcid

This compound was prepared using similar procedures as described forExample 34, Step 2 with tert-butyl(E)-3-(2-(2-((6-carbamoyl-9-(4-(5-carbamoyl-7-(3-(((3-ethoxy-3-oxopropyl)carbamoyl)oxy)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yl)oxy)ethoxy)ethoxy)propanoatereplacing methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate.LC-MS calculated for C₅₄H₆₈N₁₃O₁₃ (M+H)⁺: m/z=1106.5; found 1106.7.

Step 5:(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-8-(2-(2-(2-carboxyethoxy)ethoxy)ethoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoicAcid

This compound was prepared using similar procedures as described forExample 37, Step 2 with(E)-3-(((3-((1-(4-(8-(2-(2-(3-(tert-butoxy)-3-oxopropoxy)ethoxy)ethoxy)-6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoicacid replacing tert-butyl(6S,9S,12S,15S)-15-amino-6,9-bis(2-(tert-butoxy)-2-oxoethyl)-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-5,8,11,14-tetraoxo-12-(3-(3-((2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)guanidino)propyl)-4,7,10,13-tetraazaheptadecan-17-oate.The reaction mixture was diluted with MeOH and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as its TFAsalt. LC-MS calculated for C₅₀H₆₀N₁₃O₁₃ (M+H)⁺: m/z=1050.4; found1050.5.

Example 59.(E)-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoicAcid

Step 1: methyl(E)-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoate

This compound was prepared using similar procedures as described forExample 34, Step 1 with mono-methyl hydrogen succinate replacingmono-methyl glutarate. LC-MS calculated for C₄₈H₅₈N₁₃O₉ (M+H)⁺:m/z=960.4; found 960.5.

Step 2:(E)-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoicAcid

This compound was prepared using similar procedures as described forExample 34, Step 2 with methyl(E)-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoatereplacing methyl(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoate.LC-MS calculated for C₄₇H₅₆N₁₃O₉ (M+H)⁺: m/z=946.4; found 946.5.

Example A. IRF3 and NF-kB Activation Assays

THP-1 Dual Cells (Invivogen) were maintained in RPMI1640 medium withaddition of 10% FBS, 100 μg/ml zeocin, 10 μg/ml blasticidin. Cells wereadded in a 96-well flat bottom assay plate at 100,000 per well in 100 μLcomplete RPMI medium. Test compounds were prepared by serial dilution incomplete RPMI medium and 100 μL test compounds were transferred to eachcorresponding well. The assay plate was incubated at 37° C., 5% CO₂ for24 hours. After the overnight incubation, 20 μL of the culturesupernatants were collected, followed by addition of 180 μL ofQUANTI-Blue (Invivogen) to assess IRF3 activity. The amount of IRF3activation was assessed by reading the absorbance at 620-655 nm with amicroplate reader 2 hours later. The culture supernatant from theuntreated THP-1 cells was used as the negative control. To determine theNF-κB activation, another 20 μL of culture supernatant were transferredto a 96-well white plate, followed by addition of 50 μL of Quanti-Luc™assay solution (Invivogen). The amount of NF-κB activation induced bythe test compounds were determined by the luminescence above theuntreated control. EC₅₀ determination was performed by fitting the curveof percent control activity versus the log of the compound concentrationusing the GraphPad Prism 6.0 software.

EC₅₀ in activating IRF3 for the compounds of the Examples are presentedin Table 1 (+ refers to an EC₅₀ of <1000 nM; ++ refers to an EC₅₀ of<200 nM) and Table 2 (A refers to an EC₅₀ of <50 nM; B refers to an EC₅₀of >50 to 200 nM; c refers to an EC₅₀ of >200 to 500 nM; B refers to anEC₅₀ of >500 to 1000 nM).

TABLE 1 Example No. THP1 IRF3 EC₅₀ (nM) 1 + 2 + 3 + 4 + 5 + 6 ++ 7 + 8 +9 + 10 ++ 11 ++ 12 ++ 13 ++ 14 ++ 15 ++ 16 ++ 17 ++ 18 ++ 19 ++ 20 ++ 21++ 22 ++ 23 ++ 24 ++ 25 + 26 + 27 ++ 28 ++

TABLE 2 Example No. THP1 IRF3 EC₅₀ (nM) 1 B 2 C 4 D 5 B 6 A 7 C 8 D 9 C10 A 11 A 12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 20 A 21 A 22 A 23 B 24A 25 C 26 D 27 A 28 A 29 A 30 B 31 B 32 A 33 D 34 A 35 A 36 A 37 C 38 B39 A 40 A 41 A 42 B 43 A 44 A 45 A 46 A 47 A 48 A 49 A 50 A 51 A 52 B 53B 54 B 55 B 56 B 57 B 58 C 59 B

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, or 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2, 3, or 4independently selected R⁸ groups; U is N or CR^(U); V is N or CR^(Y); Wis N or CR^(W); Q is N or CR^(Q); wherein U═V—W=Q is selected fromCR^(U)═CR^(V)—CR^(W)═CR^(Q), N═CR^(V)—CR^(W)═CR^(Q),CR^(U)═N—CR^(W)═CR^(Q), CR^(U)═CR^(V)—N═CR^(Q), CR^(U)═CR^(V)—CR^(W)═N,N═N—CR^(W)═CR^(Q), CR^(U)═N—N═CR^(Q), CR^(U)═CR^(V)—N═N,N═CR^(V)—CR^(W)═N, N═CR^(V)—N═CR^(Q), CR^(U)═N—CR^(W)═N, N═N—CR^(W)═N,and N═CR^(V)—N═N; R^(U), R^(V), R^(W), and R^(Q) are each independentlyselected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10membered heteroaryl-C₁₋₄ alkyl, OR^(a), SR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), C(═O)OR^(a), OC(═O)R^(b), OC(═O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(═O)R^(b), NR^(c)C(═O)OR^(b),NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d),S(═O)₂R^(b), and S(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selected R⁸groups; each R^(a), R^(c), and R^(d) is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R⁸ groups; each R^(b) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selected R⁸groups; each R^(e) is independently selected from H, CN, OH, C₁₋₄ alkyl,and C₁₋₄ alkoxy; each R⁸ is independently selected from H, halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a8), SR^(a8), C(═O)R^(b8), C(═O)NR^(c8)R^(d8), C(═O)OR^(a8),OC(═O)R^(b8), OC(═O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8),NR^(c8)C(═O)OR^(b8), NR^(c8)C(═O)NR^(c8)R^(d8), C(═NR^(e))R^(b8),C(═NR^(e))NR^(c8)R^(d8), NR^(c8)C(═NR^(e))NR^(c8)R^(d8),NR^(c8)S(═O)₂R^(b8), NR^(c8)S(═O)₂NR^(c8)R^(d8), S(═O)₂R^(b8), andS(═O)₂NR^(c8)R^(d8), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R¹⁰ groups; each R^(a8), R^(c8), and R^(d8) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR¹⁰ groups; each R^(b8) is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R¹⁰ groups; each R¹⁰ is independentlyselected from H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a10), SR^(a10), C(═O)R^(b10), C(═O)NR^(c10)R^(d10),C(═O)OR^(a10), OC(═O)R^(b10), OC(═O)NR^(c10)R^(d10), NR^(c10)R^(d10),NR^(c10)C(═O)R^(b10), NR^(c10)C(═O)OR^(b10),NR^(c10)C(═O)NR^(c10)R^(d10), C(═NR^(e))R^(b10),C(═NR^(e))NR^(c10)R^(d10), NR^(c10)C(═NR^(e))NR^(c10)R^(d10),NR^(c10)S(═O)₂R^(b10), NR^(c10)S(═O)₂NR^(c10)R^(d10), S(═O)₂R^(b10), orS(═O)₂NR^(C10)R^(d10), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(G) groups; each R^(a10), R^(c11), and R^(d10) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(G) groups; each R^(b10) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selected R^(G)groups; X is N or CR^(X); Y is N or CR^(Y); Z is N or CR^(Z); wherein i)X, Y and Z are CR^(X), CR^(Y), and CR^(Z) respectively, or ii) only oneof X, Y and Z is N, or iii) only two of X, Y and Z are N; R^(X), R^(Y),and R^(Z) are each independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a0), SR^(a0), C(═O)R^(b0), C(═O)NR^(c0)R^(d0), C(═O)OR^(a10),OC(═O)R^(b0), OC(═O)NR^(c0)R^(d0), NR^(c0)R^(d0), NR^(c0)C(═O)R^(b0),NR^(c0)C(═O)OR^(b0), NR^(c0)C(═O)NR^(c0)R^(d0), C(═NR^(e))R^(b0),C(═NR^(e))NR^(c0)R^(d0), NR^(c0)C(═NR^(e))NR^(c0)R^(d0),NR^(c0)S(═O)₂R^(b0), NR^(c0)S(═O)₂NR^(c0)R^(d0), S(═O)₂R^(b0), andS(═O)₂NR^(c0)R^(d0), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by1, 2, 3, or 4 independently selected R^(G) groups; each R^(a0), R^(c0),and R^(d0) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(G) groups; each R^(b0) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(G) groups; Ring moiety A isselected from C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, and 5-10 membered heteroaryl, each of which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups; Ring moiety B is selected from C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, each ofwhich is optionally substituted by 1, 2, 3, or 4 independently selectedR^(B) groups; n is 0 or 1; m is 0 or 1; s is 0 or 1; wherein n+m+s=1 or2; when n is 1, R¹ and R² taken together form a linking group L¹; when mis 1, one of R^(A) and one of R^(B) taken together form a linking groupL²; when s is 1, R^(Q) and R⁴ taken together form a linking group L³;L¹, L², and L³ are each independently selected from -R-R-, -R-R-R-,-Cy-, -R-Cy-, -Cy-R-, -R-Cy-R-, -R-R-Cy-, -Cy-R-R-, and -Cy-R-Cy-; eachR is independently M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,C₁₋₆ alkylene-M, M-C₁₋₆ alkylene, C₁₋₆ alkylene-M-C₁₋₆ alkylene, M-C₁₋₆alkylene-M, C₂₋₆ alkenylene-M, M-C₂₋₆ alkenylene, C₂₋₆ alkenylene-M-C₂₋₆alkenylene, M-C₂₋₆ alkenylene-M, C₂₋₆ alkynylene-M, M-C₂₋₆ alkynylene,C₂₋₆ alkynylene-M-C₂₋₆ alkynylene, or M-C₂₋₆ alkynylene-M, wherein eachof said C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene isoptionally substituted by 1, 2, 3, or 4 groups independently selectedR^(G) groups; each Cy is independently selected from C₃₋₁₄ cycloalkyl,phenyl, 4-14 membered heterocycloalkyl, and 5-6 membered heteroaryl,each of which is optionally substituted by 1, 2, 3, or 4 independentlyselected R^(G) groups; each M is independently —O—, —S—, —C(O)—,—C(O)NR^(L)—, —C(O)O—, —OC(O)—, —OC(O)NR^(L)—, —NR^(L)—, -NR^(L)C(O)—,—NR^(L)C(O)O—, —NR^(L)C(O)NR^(L)—, —NR^(L)S(O)₂₋, —S(O)₂—,—S(O)₂NR^(L)—, or —NR^(L)S(O)₂NR^(L)—; provided that when M is attachedto a nitrogen atom, then M is selected from —C(O)—, —C(O)NR^(L)—,—C(O)O—, —S(O)₂—, or —S(O)₂NR^(L)—; each R^(L) is independently selectedfrom H, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, and C₁₋₃ haloalkyl; eachR^(A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1),NR^(c1)S(═O)₂R^(b2), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), andS(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(A1) groups; each R^(B) is independentlyselected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10membered heteroaryl-C₁₋₄ alkyl, OR², SR^(a2), C(═O)R^(b2),C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2), OC(═O)NR^(C2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), C(═NR^(e))R^(b2), C(═NR^(e))NR^(c2)R^(d2),NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)₂R^(b2), and S(═O)₂NR^(c2)R^(d2),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(B1) groups; each R^(a1), R^(c1), and R^(d1) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(A1) groups; each R^(b1) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(A1) groups; each R^(a2), R^(c2), and R^(d2) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or 4independently selected R^(B1) groups; each R^(b2) is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, or 3independently selected R^(B1) groups; each R^(A1) and R^(B1) isindependently selected from H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a12), SR^(a12), C(═O)R^(b12),C(═O)NR^(c12)R^(d12), C(═O)OR^(a12), OC(═O)R^(b12),OC(═O)NR^(c12)R^(d12), NR^(c12)R^(d12), NR^(c12)C(═O)R^(b12),NR^(c12)C(═O)OR^(b12), NR^(c12)C(═O)NR^(c12)R^(d12), C(═NR^(e))R^(b12),C(═NR^(e))NR^(c12)R^(d12), NR^(c12)C(═NR^(e))NR^(c12)R^(d12),NR^(c12)S(═O)₂R^(b12), NR^(c12)S(═O)₂NR^(c12)R^(d12), S(═O)₂R^(b12), andS(═O)₂NR^(c12)R^(d12), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(G) groups; each R^(a12), R^(c12), and R^(d12) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(G) groups; each R^(b12) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selected R^(G)groups; R² is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, or 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted by1, 2, 3, or 4 independently selected R^(2a) groups; R³ is H, C₁₋₄ alkylor C₁₋₄ haloalkyl; R⁴ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4), C(═O)OR^(a4),OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(═O)R^(b4),NR^(c4)C(═O)OR^(b4), NR^(c4)C(═O)NR^(c4)R^(d4), C(═NR^(e))R^(b4),C(═NR^(e))NR^(c4)R^(d4), NR^(c4)C(═NR^(e))NR^(c4)R^(d4)NR^(c4)S(═O)₂R^(b4), NR^(c4)S(═O)₂NR^(c4)R^(d4), S(═O)₂R^(b4), orS(═O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynylC₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(4a) groups; R⁵ is H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)NR^(c5)R^(d5), C(═O)OR^(a5),OC(═O)R^(b5), OC(═O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(═O)R^(b8),NR^(c5)C(═O)OR^(b5), NR^(c5)C(═O)NR^(c5)R^(d5), C(═NR^(e))R^(b5),C(═NR^(e))NR^(c5)R^(d5), NR^(c5)C(═NR^(e))NR^(c5)R^(d5),NR^(c5)S(═O)₂R^(b5), NR^(c5)S(═O)₂NR^(c5)R^(d5), S(═O)₂R^(b5), orS(═O)₂NR^(c5)R^(d5), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(5a) groups; R⁶ is H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a6), SR^(a6), C(═O)R^(b6), C(═O)NR^(c6)R^(d6), C(═O)OR^(a6),OC(═O)R^(b6), OC(═O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(═O)R^(b6),NR^(c6)C(═O)OR^(b6), NR^(c6)C(═O)NR^(c6)R^(d6), C(═NR^(e))R^(b6),C(═NR^(e))NR^(c6)R^(d6), NR^(c6)C(═NR^(e))NR^(c6)R^(d6),NR^(c6)S(═O)₂R^(b6), NR^(c6)S(═O)₂NR^(c6)R^(d6), S(═O)₂R^(b6), orS(═O)₂NR^(c6)R^(d6), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(6a) groups; R⁷ is H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a7), SR^(a7), C(═O)R^(b7), C(═O)NR^(c7)R^(d7), C(═O)OR^(a7),OC(═O)R^(b7), OC(═O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(═O)R^(b7),NR^(c7)C(═O)OR^(b7), NR^(c7)C(═O)NR^(c7)R^(d7), C(═NR^(e))R^(b7),C(═NR^(e))NR^(c7)R^(d7), NR^(c7)C(═NR^(e))NR^(c7)R^(d7),NR^(c7)S(═O)₂R^(b7), NR^(c7)S(═O)₂NR^(c7)R^(d7), S(═O)₂R^(b7), orS(═O)₂NR^(c7)R^(d7), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(7a) groups; each R^(a4), R^(c4), and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(4a) groups; each R^(b4) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(4a) groups; each R^(a5), R^(c5),and R^(d5) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(5a) groups; each R^(b5) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(5a) groups; each R^(a6), R^(c6),and R^(d6) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(6a) groups; each R^(b6) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynylC₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(6a) groups; each R^(a7), R^(c7),and R^(d7) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(7a) groups; each R^(b7) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, or 3 independently selected R^(7a) groups; each R^(2a), R^(4a),R^(5a), R^(6a), and R^(7a) are independently selected from H, halo, CN,NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a9), SR^(a9), C(═O)R^(b9), C(═O)NR^(c9)R^(d9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NR^(c9)C(═O)OR^(b9), NR^(c9)C(═O)NR^(c9)R^(d9), C(═NR^(e))R^(b9),C(═NR^(e))NR^(c9)R^(d9), NR^(c9)C(═NR^(e))NR^(c9)R^(d9),NR^(c9)S(═O)₂R^(b9), NR^(c9)S(═O)₂NR^(c9)R^(d9), S(═O)₂R^(b9), andS(═O)₂NR^(c9)R^(d9), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R¹¹ groups; each R^(a9), R^(c9), and R^(d9) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR¹¹ groups; each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R¹¹ groups; each R¹¹ is independentlyselected from H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a11), SR^(a11), C(═O)R^(b11), C(═O)NR^(c11)R^(d11),C(═O)OR^(a11), OC(═O)R^(b11), OC(═O)NR^(c11)R^(d11), NR^(c11)R^(d11),NR^(c11)C(═O)R^(b11), NR^(c11)C(═O)OR^(b11),NR^(c11)C(═O)NR^(c11)R^(d11), C(═NR^(e))R^(b11),C(═NR^(e))NR^(c11)R^(d11), NR^(c11)C(═NR^(e))NR^(c11)R^(d11),NR^(c11)S(═O)₂R^(b11), NR^(c11)S(═O)₂NR^(c11)R^(d11), S(═O)₂R^(b11), andS(═O)₂NR^(c11)R^(d1), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(G) groups; each R^(a11), R^(c11), and R^(d11) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(G) groups; each R^(b11) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selected R^(G)groups; and each R^(G) is independently selected from OH, NO₂, CN, halo,C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl,C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl,C₁₋₄ alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.
 2. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein U is CR^(U).
 3. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(U) is H, halo, CN, C₁₋₆ alkyl,OR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d), S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d).4. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein V is CR^(V).
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein W is CR^(W).
 6. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R^(W) is H, halo, CN, C₁₋₆ alkyl, OR^(a), C(═O)R^(b),C(═O)NR^(c)R^(d), S(═O)₂R^(b), or S(═O)₂NR^(c)R^(d).
 7. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Q isCR^(Q).
 8. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein each R^(a), R^(c), and R^(d) is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkylis optionally substituted with 1, 2, 3, or 4 independently selected R⁸groups; each R^(b) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,or 3 independently selected R⁸ groups; and each R⁸ is independentlyselected from OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl,C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,and di(C₁₋₃ alkyl)amino.
 9. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is H, C₁₋₆ alkyl,or C₁₋₆ haloalkyl.
 10. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(V) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, or C(═O)NR^(c)R^(d), wherein R^(c) and R^(d) areeach independently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl. 11.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R^(Q) is H or OR^(a), wherein R^(a) is selected from H, C₁₋₆alkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆alkyl is optionally OH or C₁₋₃ alkoxy.
 12. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein X is CR^(X).
 13. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R^(X) is selected from H, D, halo, CN, C₁₋₆ alkyl, and C₁₋₆haloalkyl.
 14. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R^(X) is H or C₁₋₆ alkyl.
 15. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Y isCR^(Y).
 16. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R^(Y) is selected from H, halo, and CN.
 17. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Y is N.
 18. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Z is CR^(Z).
 19. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R^(Z) isselected from H, halo, and CN.
 20. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Z is N.
 21. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl.
 22. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H,D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, OR^(a4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4),C(═O)OR^(a4), OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)OR^(b4), NR^(c4)C(═O)NR^(c4)R^(d4),NR^(c4)S(═O)₂R^(b4), NR^(c4)S(═O)₂NR^(c4)R^(d4), S(═O)₂R^(b4), orS(═O)₂NR^(c4)R^(d4), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(4a) groups.
 23. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(a4), R^(c4),and R^(d4) is independently selected from H, C₁₋₆ alkyl, and C₁₋₆haloalkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1, 2,3, or 4 independently selected R^(4a) groups; and each R^(b4) isindependently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl, wherein saidC₁₋₆ alkyl is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4a) groups.
 24. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵, R⁶, and R⁷ areeach independently selected from H, halo, CN, OH, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, carbamyl, C₁₋₆ alkylcarbamyl, and di(C₁₋₆ alkyl)carbamyl.25. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Ring moiety A is 5 membered heteroaryl, which isoptionally substituted by 1, 2, 3, or 4 independently selected R^(A)groups.
 26. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Ring moiety A is a pyrazole ring, which isoptionally substituted by 1, 2, or 3 independently selected R^(A)groups.
 27. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein each R^(A) is independently selected from halo,CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.
 28. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Ring moiety B is 5membered heteroaryl, which is optionally substituted by 1, 2, 3, or 4independently selected R^(B) groups.
 29. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Ring moiety B is apyrazole ring, which is optionally substituted by 1, 2, or 3independently selected R^(B) groups.
 30. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(B) isindependently selected from halo, CN, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.31. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein L¹, L², and L³ are each independently selected from-R-R- and -R-R-R-.
 32. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R is independently C₁₋₆ alkyleneor C₂₋₆ alkenylene.
 33. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein L¹, L², and L³ are each independently—CH₂—CH═CH—CH₂—.
 34. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein: U is CR^(U); V is CR^(V); W is CR^(W);Q is CR^(Q); R^(U) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, or C(═O)NR^(c)R^(d); R^(V) is H, halo, CN, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, or C(═O)NR^(c)R^(d); R^(W) is H, halo, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, or C(═O)NR^(c)R^(d); R^(Q) is H,halo, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, or C(═O)NR^(c)R^(d);each R^(c) and R^(d) is independently selected from H, C₁₋₆ alkyl, andC₁₋₆ haloalkyl; X is CR^(X); R^(X) is selected from H, D, halo, CN, C₁₋₆alkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkyl; Y is N or CR^(Y); R^(Y) isselected from H, D, halo, CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkyl; Z is N; R¹ is H, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; R², R⁴, R⁵,R⁶, and R⁷ are each independently selected from H, halo, CN, OH, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, carbamyl, C₁₋₆ alkylcarbamyl, anddi(C₁₋₆ alkyl)carbamyl; R³ is H; Ring moiety A is a pyrazole ring, whichis optionally substituted by 1, 2, or 3 independently selected R^(A)groups; Ring moiety B is a pyrazole ring, which is optionallysubstituted by 1, 2, or 3 independently selected R^(B) groups; eachR^(A) is independently selected from halo, CN, C₁₋₆ alkyl, and C₁₋₆haloalkyl; each R^(B) is independently selected from halo, CN, C₁₋₆alkyl, and C₁₋₆ haloalkyl; n is 0 or 1; m is 0 or 1; s is 0 or 1;wherein n+m+s=1 or 2; when n is 1, R¹ and R² taken together form alinking group L¹; when m is 1, one of R^(A) and one of R^(B) takentogether form a linking group L²; when s is 1, R^(Q) and R⁴ takentogether form a linking group L³; L¹ is —CH₂—CH═CH—CH₂—; L² is—CH₂—CH═CH—CH₂—; and L³ is —CH₂—CH═CH—CH₂—.
 35. The compound of claim 1,or a pharmaceutically acceptable salt thereof, having Formula (II):

or a pharmaceutically acceptable salt thereof.
 36. The compound of claim1, or a pharmaceutically acceptable salt thereof, having Formula (IIa):

or a pharmaceutically acceptable salt thereof.
 37. The compound of claim1, or a pharmaceutically acceptable salt thereof, having Formula (VIII):

or a pharmaceutically acceptable salt thereof.
 38. The compound of claim1, or a pharmaceutically acceptable salt thereof, having Formula (IX):

or a pharmaceutically acceptable salt thereof.
 39. A compound of Formula(X):

or a pharmaceutically acceptable salt thereof, wherein: R^(U), R^(V),and R^(W) are each independently selected from H, D, OH, NO₂, CN, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆alkyl, HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl,C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino; R^(Q) isselected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, —C₁₋₆ alkylene-R⁸⁰, —C₁₋₆alkylene-R⁹⁰, —C₁₋₆ alkylene-OR⁸⁰, —C₁₋₆ alkylene-NHR⁸⁰, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a), OR^(f), SR^(a), C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a),OC(═O)R^(b), OC(═O)NR^(c)R^(d), NR^(C)R^(d), NR^(c)C(═O)R^(b),NR^(c)C(═O)OR^(b), NR^(c)C(═O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(═O)₂R^(b),NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), and S(═O)₂NR^(c)R^(d), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R⁸ groups; R^(a), R^(c), and R^(d) are each independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R⁸ groups; R^(b) is selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selected R⁸groups; each R^(e) is independently selected from H, CN, OH, C₁₋₄ alkyl,and C₁₋₄ alkoxy; R^(f) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl,which are each optionally substituted with 1 substituent selected fromR⁸⁰, —OR⁸⁰, R⁹⁰, and —NHR⁸⁰; each R⁸ is independently selected from H,halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a8), SR^(a8), C(═O)R^(b8), C(═O)NR^(c8)R^(d8), C(═O)OR^(a8),OC(═O)R^(b8), OC(═O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8),NR^(c8)C(═O)OR^(b8), NR^(c8)C(═O)NR^(c8)R^(d8), C(═NR^(e))R^(b8),C(═NR^(e))NR^(c8)R^(d8), NR^(c8)C(═NR^(e))NR^(c8)R^(d8),NR^(c8)S(═O)₂R^(b8), NR^(c8)S(═O)₂NR^(c8)R^(d8), S(═O)₂R^(b8), andS(═O)₂NR^(c8)R^(d8), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R¹⁰ groups; each R^(a8), R^(c8), and R^(d8) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR¹⁰ groups; each R^(b8) is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R¹⁰ groups; each R¹⁰ is independentlyselected from H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a10), SR^(a10), C(═O)R^(b10), C(═O)NR^(c10)R^(d10),C(═O)OR^(a10), OC(═O)R^(b10), OC(═O)NR^(c10)R^(d10), NR^(c10)R^(d10),NR^(c10)C(═O)R^(b10), NR^(c10)C(═O)OR^(b10),NR^(c10)C(═O)NR^(c10)R^(d10), C(═NR^(e))R^(b10),C(═NR^(e))NR^(c10)R^(d10), NR^(c10)C(═NR^(e))NR^(c10)R^(d10),NR^(c10)S(═O)₂R^(b10), NR^(c10)S(═O)₂NR^(c10)R^(d10), S(═O)₂R^(b10), orS(═O)₂NR^(c10)R^(d10), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(G) groups; each R^(a10), R^(c10), and R^(d10) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(G) groups; each R^(b10) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selected R^(G)groups; R⁸⁰ is a linear peptide chain having 2-6 amino acids; R⁹⁰ is alinear chain of formula —(O—C₂₋₄ alkylene)_(z)-R^(G), wherein z is 1, 2,3, 4, 5, or 6; Y is N or CR^(Y); Z is N or CR^(Z); R^(X), R^(Y), andR^(Z) are each independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl;Ring moiety A is 5-membered heteroaryl, which is optionally substitutedby 1, 2, 3, or 4 independently selected R^(A) groups; Ring moiety B is5-membered heteroaryl, which is optionally substituted by 1, 2, 3, or 4independently selected R^(B) groups; L¹ is selected from -R-R- and-R-R-R-; each R is independently M, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆alkynylene, C₁₋₆ alkylene-M, M-C₁₋₆ alkylene, C₁₋₆ alkylene-M-C₁₋₆alkylene, M-C₁₋₆ alkylene-M, C₂₋₆ alkenylene-M, M-C₂₋₆ alkenylene, C₂₋₆alkenylene-M-C₂₋₆ alkenylene, M-C₂₋₆ alkenylene-M, C₂₋₆ alkynylene-M,M-C₂₋₆ alkynylene, C₂₋₆ alkynylene-M-C₂₋₆ alkynylene, or M-C₂₋₆alkynylene-M, wherein each of said C₁₋₆ alkylene, C₂₋₆ alkenylene, andC₂₋₆ alkynylene is optionally substituted by 1, 2, 3, or 4 groupsindependently selected R^(G) groups; each M is independently —O—, —S—,—C(O)—, —C(O)NR^(L)—, —C(O)O—, —OC(O)—, —OC(O)NR^(L)—, —NR^(L)—,—NR^(L)C(O)—, —NR^(L)C(O)O—, —NR^(L)C(O)NR^(L)—, —NR^(L)S(O)₂₋, —S(O)₂—,—S(O)₂NR^(L)—, or —NR^(L)S(O)₂NR^(L)—; provided that when M is attachedto a nitrogen atom, then M is selected from —C(O)—, —C(O)NR^(L)—,—C(O)O—, —S(O)₂—, or —S(O)₂NR^(L)—; each R^(L) is independently selectedfrom H, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, and C₁₋₃ haloalkyl; eachR^(A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₄cycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(G) groups; each R^(B) is independentlyselected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₄ cycloalkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(G)groups; R⁵, R⁶, and R⁷ are each independently selected from H, D, OH,NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₆ alkoxy-C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; R⁴ is H, D, halo, CN, NO₂, C₁₋₆ alkyl, —C₁₋₆alkylene-R⁸⁰, —C₁₋₆ alkylene-R⁹⁰, —C₁₋₆ alkylene-OR⁸⁰, —C₁₋₆alkylene-NHR⁸⁰, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄alkyl, OR^(a4), OR^(f4), SR^(a4), C(═O)R^(b4), C(═O)NR^(c4)R^(d4),C(═O)OR^(a4), OC(═O)R^(b4), OC(═O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)OR^(b4), NR^(c4)C(═O)NR^(c4)R^(d4),C(═NR^(e))R^(b4), C(═NR^(e))NR^(c4)R^(d4),NR^(c4)C(═NR^(e))NR^(c4)R^(d4), NR^(c4)S(═O)₂R^(b4),NR^(c4)S(═O)₂NR^(c4)R^(d4), S(═O)₂R^(b4), or S(═O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted by 1, 2, 3, or 4 independently selectedR^(4a) groups; each R^(a4), R^(c4), and R^(d4) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(4a) groups; each R^(b4) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selectedR^(4a) groups; R^(f4) is selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl,which are each optionally substituted with 1 substituent selected fromR⁸⁰, R⁹⁰, —OR⁸⁰, and —NHR⁸⁰; each R^(4a) is independently selected fromH, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a9), SR^(a9), C(═O)R^(b9), C(═O)NR^(c9)R^(d9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NR^(c9)C(═O)OR^(b9), NR^(c9)C(═O)NR^(c9)R^(d9), C(═NR^(e))R^(b9),C(═NR^(e))NR^(c9)R^(d9) NR^(c9)C(═NR^(e))NR^(c9)R^(d9),NR^(c9)S(═O)₂R^(b9), NR^(c9)S(═O)₂NR^(c9)R^(d9), S(═O)₂R^(b9), andS(═O)₂NR^(c9)R^(d9), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R¹¹ groups; each R^(a9), R^(c9), and R^(d9) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR¹¹ groups; each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, or 3 independently selected R¹¹ groups; R^(f4) is selected from C₁₋₆alkyl and C₁₋₆ haloalkyl, which are each optionally substituted with 1substituent selected from R⁸⁰, —OR⁸⁰, and —NHR⁸⁰; each R¹¹ isindependently selected from H, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, 5-6membered heteroaryl-C₁₋₄ alkyl, OR^(a11), SR^(a11), C(═O)R^(b11),C(═O)NR^(c11)R^(d11), C(═O)OR^(a11), OC(═O)R^(b11),OC(═O)NR^(c11)R^(d11), NR^(c11)R^(d11), NR^(c11)C(═O)R^(b11),NR^(c11)C(═O)OR^(b11), NR^(c11)C(═O)NR^(c11)R^(d11), C(═NR^(e))R^(b11),C(═NR^(e))NR^(c11)R^(d11), NR^(c11)C(═NR^(e))NR^(c11)R^(d11),NR^(c11)S(═O)₂R^(b11), NR^(c11)S(═O)₂NR^(c11)R^(d11), S(═O)₂R^(b11), andS(═O)₂NR^(c11)R^(d11), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted by 1, 2, 3, or 4 independentlyselected R^(G) groups; each R^(a11), R^(c11), and R^(d11) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl,4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(G) groups; each R^(b11) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, or 3 independently selected R^(G)groups; and each R^(G) is independently selected from H, D, OH, NO₂, CN,halo, C₁₋₃ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃alkyl, HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl,C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl,C₁₋₄ alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.
 40. Thecompound of claim 39, wherein: R^(Q) is selected from H, C₁₋₆ alkyl,OR^(a), and OR^(f), wherein said C₁₋₆ alkyl is optionally substituted by1 or 2 independently selected R⁸ groups; R^(a) is selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl areeach optionally substituted with 1 or 2 independently selected R⁸groups; R^(f) is C₁₋₆ alkyl which is substituted with 1 substituentselected from R⁹⁰ and —NHR⁸⁰; each R⁸ is independently selected from H,halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a8), C(═O)OR^(a8),OC(═O)R^(b8), OC(═O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8),NHC(═O)NHR^(d8), NR^(c8)S(═O)₂R^(b8), and NR^(c8)C(═O)OR^(b8); eachR^(a8), R^(c8), and R^(d8) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,and 5-6 membered heteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl areeach optionally substituted with 1 or 2 independently selected R¹⁰groups; each R^(b8) is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and5-6 membered heteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl areeach optionally substituted with 1 or 2 independently selected R¹⁰groups; each R¹⁰ is independently selected from H, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, OR^(a10), NR^(c10)R^(d10), and C(═O)OR^(a10), whereinsaid C₁₋₆ alkyl is optionally substituted by 1 or 2 independentlyselected R^(G) groups; each R^(a10) is independently selected from H andC₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1 or2 independently selected R^(G) groups; R⁸⁰ is a linear peptide chainhaving 2-4 amino acids; and R⁹⁰ is a linear chain of formula —(O—C₂₋₄alkylene)_(z)-R^(G), wherein z is 1, 2, 3, or
 4. 41. The compound ofclaim 39, wherein: R⁴ is selected from H, C₁₋₆ alkyl, OR^(a4), andOR^(f4), wherein said C₁₋₆ alkyl is optionally substituted by 1 or 2independently selected R^(4a) groups; R^(a4) is selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl areeach optionally substituted with 1 or 2 independently selected R^(4a)groups; R^(f4) is C₁₋₆ alkyl which is substituted with 1 substituentselected from R⁹⁰ and —NHR⁸⁰; each R^(4a) is independently selected fromH, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NHC(═O)NHR^(d8), NR^(c9)S(═O)₂R^(b9), and NR^(c9)C(═O)OR^(b9); eachR^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,and 5-6 membered heteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl areeach optionally substituted with 1 or 2 independently selected R¹¹groups; each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and5-6 membered heteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl areeach optionally substituted with 1 or 2 independently selected R¹¹groups; each R¹¹ is independently selected from H, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, OR^(a11), NR^(c11)R^(d11), and C(═O)OR^(a11), whereinsaid C₁₋₆ alkyl is optionally substituted by 1 or 2 independentlyselected R^(G) groups; each R^(a11) is independently selected from H andC₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1 or2 independently selected R^(G) groups; each R^(c11) and R^(d11)independently selected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl isoptionally substituted with 1 or 2 independently selected R^(G) groups;R⁸⁰ is a linear peptide chain having 2-4 amino acids; and R⁹⁰ is alinear chain of formula —(O—C₂₋₄ alkylene)_(z)-R^(G), wherein z is 1, 2,3, or 4
 42. The compound of claim 39, wherein: R^(V) is H, halo, CN,C₁₋₄ alkyl, C₁₋₄ haloalkyl, carbamyl, or C₁₋₄ alkylcarbamyl; R^(U) andR^(W) are each independently selected from H, halo, CN, C₁₋₄ alkyl, andC₁₋₄ haloalkyl; R^(Q) is selected from H, C₁₋₆ alkyl, OR^(a), andOR^(f), wherein said C₁₋₆ alkyl is optionally substituted by 1 or 2independently selected R⁸ groups; R^(a) is selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, whereinsaid C₁₋₆ alkyl and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl are eachoptionally substituted with 1 or 2 independently selected R⁸ groups;R^(f) is C₁₋₆ alkyl which is substituted with 1 substituent selectedfrom R⁹⁰ and —NHR⁸⁰; each R⁸ is independently selected from H, halo, CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a8), C(═O)OR^(a8), OC(═O)R^(b8),OC(═O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8), NHC(═O)NHR^(d8),NR^(c8)S(═O)₂R^(b8), and NR^(c8)C(═O)OR^(b8); each R^(a8), R^(c8), andR^(d8) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 independently selected R¹⁰ groups;each R^(b8) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl are eachoptionally substituted with 1 or 2 independently selected R¹⁰ groups;each R¹⁰ is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a10), NR^(c10)R^(d10), and C(═O)OR^(a10), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selectedR^(G) groups; each R^(a10) is independently selected from H and C₁₋₆alkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1 or 2independently selected R^(G) groups; R⁸⁰ is a linear peptide chainhaving 2-4 amino acids; R⁹⁰ is a linear chain of formula —(O—C₂₋₄alkylene)_(z)-R^(G), wherein z is 1, 2, 3, or 4; Y is N or CR^(Y); Z isN or CR^(Z); wherein at least one of Y or Z is N; R^(X), R^(Y), andR^(Z) are each independently selected from H, halo, CN, C₁₋₃ alkyl, andC₁₋₃ haloalkyl; Ring moiety A is a pyrazole ring, which is optionallysubstituted by 1, 2, or 3 independently selected R^(A) groups; Ringmoiety B is a pyrazole ring, which is optionally substituted by 1, 2, or3 independently selected R^(B) groups; L¹ is selected from -R-R- and-R-R-R-; each R is independently C₁₋₃ alkylene or C₂₋₃ alkenylene; eachR^(A) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; eachR^(B) is independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; R⁴is selected from H, C₁₋₆ alkyl, OR^(a4), and OR^(f4), wherein said C₁₋₆alkyl is optionally substituted by 1 or 2 independently selected R^(4a)groups; R⁶ is H, halo, CN, C₁₋₄ alkyl, C₁₋₄ haloalkyl, carbamyl, or C₁₋₄alkylcarbamyl; R⁵ and R⁷ are each independently selected from H, halo,CN, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; R^(a4) is selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl areeach optionally substituted with 1 or 2 independently selected R⁸groups; R^(f4) is C₁₋₆ alkyl which is substituted with 1 substituentselected from R⁹⁰ and —NHR⁸⁰; each R^(4a) is independently selected fromH, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a9), C(═O)OR^(a9),OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9),NHC(═O)NHR^(d9), NR^(c9)S(═O)₂R^(b9), and NR^(c9)C(═O)OR^(b9); eachR^(a9), R^(c9), and R^(d9) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl,and 5-6 membered heteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl areeach optionally substituted with 1 or 2 independently selected R¹¹groups; each R^(b9) is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and5-6 membered heteroaryl, wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl areeach optionally substituted with 1 or 2 independently selected R¹¹groups; each R¹¹ is independently selected from H, halo, CN, C₁₋₆ alkyl,C₁₋₆ haloalkyl, OR^(a1), NR^(c11)R^(d11), and C(═O)OR^(a11), whereinsaid C₁₋₆ alkyl is optionally substituted by 1 or 2 independentlyselected R^(G) groups; each R^(a11) is independently selected from H andC₁₋₆ alkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1 or2 independently selected R^(G) groups; each R^(c11) and R^(d11)independently selected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl isoptionally substituted with 1 or 2 independently selected R^(G) groups;each R^(G) is independently selected from H, D, OH, NO₂, CN, halo, C₁₋₃alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl,HO—C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkoxy,C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkylsulfonylamino,aminosulfonyl, C₁₋₃ alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₃alkylaminocarbonylamino, and di(C₁₋₃ alkyl)aminocarbonylamino.
 43. Thecompound of claim 39, wherein: R^(V) is H or carbamyl; R^(U) and R^(W)are each independently selected from H, halo, CN, and C₁₋₃ alkyl; R^(Q)is selected from H, C₁₋₆ alkyl, OR^(a), and OR^(f); R^(a) is selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl and 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl are each optionally substituted with 1 or 2independently selected R⁸ groups; each R⁸ is independently selected fromH, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a8), C(═O)OR^(a8),OC(═O)R^(b8), OC(═O)NR^(c8)R^(d8), NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8),NHC(═O)NHR^(d8), NR^(c8)S(═O)₂R^(b8), and NR^(c8)C(═O)OR^(b8); eachR^(a8), R^(c8), and R^(d8) is independently selected from H, C₁₋₆ alkyl,and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl is optionally substitutedwith 1 or 2 independently selected R¹⁰ groups; each R^(b8) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, and 5-memberedheteroaryl, wherein said C₁₋₆ alkyl and 5-membered heteroaryl are eachoptionally substituted with 1 or 2 independently selected R¹⁰ groups;each R¹⁰ is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a10), NR^(c10)R^(d10), and C(═O)OR^(a10), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selectedR^(G) groups; each R^(a10) is independently selected from H and C₁₋₆alkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1 or 2independently selected R^(G) groups; Y is N or CR^(Y); Z is N or CR^(Z);wherein at least one of Y or Z is N; R^(X), R^(Y), and R^(Z) are eachindependently selected from H, halo, CN, C₁₋₃ alkyl, and C₁₋₃ haloalkyl;Ring moiety A is a pyrazole ring, which is optionally substituted by 1or 2 independently selected R^(A) groups; Ring moiety B is a pyrazolering, which is optionally substituted by 1 or 2 independently selectedR^(B) groups; L¹ is C₃₋₆ alkenylene; each R^(A) is independentlyselected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(B) is independentlyselected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; R⁴ is selected from H, C₁₋₆alkyl, OR^(a4), and OR^(f4), wherein said C₁₋₆ alkyl is optionallysubstituted by 1 or 2 independently selected R^(4a) groups; R⁶ is H orcarbamyl; R⁵ and R⁷ are each independently selected from H, halo, CN,and C₁₋₃ alkyl; R^(a4) is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,and 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyland 4-7 membered heterocycloalkyl-C₁₋₄ alkyl are each optionallysubstituted with 1 or 2 independently selected R⁸ groups; R^(f4) is C₁₋₆alkyl which is substituted with 1 substituent selected from R⁹⁰ and—NHR⁸⁰; each R^(4a) is independently selected from H, halo, CN, C₁₋₆alkyl, C₁₋₆ haloalkyl, OR^(a9), OC(═O)R^(b9), OC(═O)NR^(c9)R^(d9),NR^(c9)R^(d9), NR^(c9)C(═O)R^(b9), NHC(═O)NHR^(d9), NR^(c9)S(═O)₂R^(b9),and NR^(c9)C(═O)OR^(b9); R⁸⁰ is a linear peptide chain having 2-4 aminoacids; R⁹⁰ is a linear chain of formula —(O—C₂₋₄ alkylene)_(z)-R^(G),wherein z is 1, 2, 3, or 4; each R^(a9), R^(c9), and R^(d9) isindependently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl, whereinsaid C₁₋₆ alkyl is optionally substituted with 1 or 2 independentlyselected R¹¹ groups; each R^(b9) is independently C₁₋₆ alkyl, which isoptionally substituted with 1 or 2 independently selected R¹¹ groups;each R¹¹ is independently selected from H, halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, OR^(a11), NR^(C11)R^(d11), and C(═O)OR^(a11), wherein saidC₁₋₆ alkyl is optionally substituted by 1 or 2 independently selectedR^(G) groups; each R^(a11) is independently selected from H and C₁₋₆alkyl, wherein said C₁₋₆ alkyl is optionally substituted with 1 or 2independently selected R^(G) groups; each R^(c11) and R^(d11)independently selected from H and C₁₋₆ alkyl, wherein said C₁₋₆ alkyl isoptionally substituted with 1 or 2 independently selected R^(G) groups;and each R^(G) is independently selected from H, OH, CN, halo, C₁₋₃alkyl, C₁₋₃ alkoxy, C₁₋₃ amino, C₁₋₃ alkylamino, di(C₁₋₃ alkyl)amino,and carboxy.
 44. The compound of claim 39, or a pharmaceuticallyacceptable salt thereof, wherein Ring moiety A is a pyrazole ring, whichis optionally substituted by 1 or 2 independently selected R^(A) groups;Ring moiety B is a pyrazole ring, which is optionally substituted by 1or 2 independently selected R^(B) groups; each R^(A) and R^(B) isindependently selected from C₁₋₄ alkyl; and L¹ is —CH₂—CH═CH—CH₂—. 45.The compound of claim 1, selected from:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-1-(4-(2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazole-5-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1,3-dimethyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;and(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamide;or a pharmaceutically acceptable salt thereof.
 46. The compound of claim1, selected from:(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(3-methyl-1-propyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-hydroxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrido[2,3-b]indole-6-carboxamide;(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-5-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-4-fluoro-5H-pyrido[4,3-b]indole-8-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-3-cyano-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2,3-b]indole-6-carboxamide;(E)-5-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-4-cyano-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-5H-pyrido[4,3-b]indole-8-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;and(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-hydroxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;or a pharmaceutically acceptable salt thereof.
 47. The compound of claim39, selected from:(E)-9-(4-(5-carbamoyl-7-(3-cyanopropoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-isopropoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-(4-methylpiperazin-1-yl)propoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-3-fluoro-9H-pyrido[2,3-b]indole-6-carboxamide;(E)-9-(4-(7-(3-aminopropoxy)-5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-5-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-5-oxopentanoicacid;(E)-2-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethyl1-ethyl-3-methyl-1H-pyrazole-5-carboxylate;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-hydroxyethoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;(6S,9S,12S,15S)-15-amino-1-((5-carbamoyl-1-((E)-4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)-6,9-bis(carboxymethyl)-12-(3-guanidinopropyl)-5,8,11,14-tetraoxo-4,7,10,13-tetraazaheptadecan-17-oicacid;(E)-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide;(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)propanoicacid;(E)-2-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)oxy)aceticacid;(E)-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)carbamoyl)glycine;(S,E)-3-amino-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoicacid;(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoicacid;(E)-3-(2-(2-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)ethoxy)ethoxy)propanoicacid;(E)-4-(N-(3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)sulfamoyl)butanoicacid;(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoicacid;(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoicacid;(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoicacid;(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoicacid;(E)-5-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylamino)-5-oxopentanoicacid;(E)-3-(3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propylcarbamoyloxy)propanoicacid;(E)-3-((3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propoxy)carbonylamino)propanoicacid;(E)-3-(2-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethoxy)ethoxy)propanoicacid;(E)-3-(2-(2-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-methoxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethoxy)ethoxy)ethoxy)propanoicacid;(E)-4-(4-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethyl)piperidin-1-yl)butanoicacid;(E)-2-(4-(2-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)ethyl)piperidine-1-carbonyloxy)aceticacid;(E)-3-((3-(6-carbamoyl-9-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-enyl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-8-yloxy)propoxy)carbonylamino)propanoicacid;(E)-3-(((3-((5-carbamoyl-1-(4-(6-carbamoyl-8-(2-(2-(2-carboxyethoxy)ethoxy)ethoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propoxy)carbonyl)amino)propanoicacid; and(E)-4-((3-((5-carbamoyl-1-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxypropoxy)-9H-pyrimido[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)propyl)amino)-4-oxobutanoicacid; or a pharmaceutically acceptable salt thereof.
 48. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 49. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, for use in therapy.
 50. Use of the compound ofclaim 1, or pharmaceutically acceptable salt thereof, in the manufactureof a medicament for the treatment of a STING-mediated disease.
 51. Amethod of treating a STING-mediated disease or disorder comprisingadministering a therapeutically effective amount of a compound of claim1, or pharmaceutically acceptable salt thereof, to a human in needthereof.
 52. The method of claim 51, wherein the disease or disorder iscancer.
 53. The method of claim 51, wherein the disease or disorder isan infectious disease.
 54. The method of claim 51, wherein the diseaseor disorder is sickle cell disease or sickle cell anemia.